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Atopic dermatitis (AD) is a common inflammatory skin disease characterized by recurrent eczema and chronic itching, affecting a significant portion of the global population. This study investigated the effects of Corydalis Tuber 70% ethanol extract (CTE) on tumor necrosis factor-α- and interferon-γ (TI)-stimulated human keratinocytes (HaCaT) and a house dust mite-induced AD mouse model, elucidating its mechanism via transcriptome analysis. A total of 13 compounds, including columbamine, corydaline, dehydrocorydaline, and glaucine, were identified in CTE using ultra performance liquid chromatography-tandem mass spectrometry. CTE downregulated pathways related to cytokine signaling and chemokine receptors in TI-stimulated HaCaT cells. It significantly inhibited C-C motif chemokine ligand (CCL)5, CCL17, and CCL22 levels by blocking the Janus kinase-signal transducers and activators of transcription and nuclear factor kappa-light-chain-enhancer of activated B cells pathways. In the AD mouse model, topical CTE significantly decreased dermatitis scores, epidermal thickening, and inflammatory cell infiltration. Plasma levels of histamine, immunoglobulin E, CCL17, CCL22, corticosterone, and cortisol were reduced. Lesions showed decreased thymic stromal lymphopoietin, CD4 + T cells, interleukin-4, and intercellular adhesion molecule-1 expression. The findings demonstrate that CTE alleviates AD by modulating inflammatory mediators, cytokines, and chemokines, reducing inflammatory cell infiltration, and alleviating stress-related factors.

Natural α-spinasterol is well known for its various biological activities. In this study, we investigated the anti-inflammatory effects of newly synthesized α-spinasterol derivatives by tracking the expression of CCL17 and CCL22 chemokines, which serve as biomarkers for immune cell trafficking in skin inflammation. Initially, the 3-epimer of α-spinasterol, which results from inversion of stereochemistry at the C-3 position of α-spinasterol, was synthesized using the Mitsunobu reaction. Subsequently, new compounds were synthesized by introducing azido, amino, and amide groups at the C-3 position of α-spinasterol or 3-epi-α-spinasterol. The anti-inflammatory activity of these compounds was evaluated by examining their inhibitory effects on the mRNA expression of CCL17 and CCL22. Among these derivatives, 3α-8, 3α-12b, and 3α-12c exhibited potential anti-inflammatory activity in vitro, compared to α-spinasterol. Furthermore, compound 3α-8 showed even greater activity than 3α-12b and 3α-12c, underscoring its potential as a highly effective agent. These results suggest that the newly synthesized α-spinasterol derivatives hold promise as candidates for skin inflammation therapeutics., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Oral cancer is a malignant tumor of the oral cavity, with regulatory T cell (Treg) infiltration associated with poor prognosis. Ginkgolide B (GB) has demonstrated effects on lipid metabolism; however, its potential immunotherapeutic effects on oral cancer have not been elaborated., Purpose: This study aimed to explore the immunotherapeutic effects of Ginkgolide B (GB) in oral cancer., Study Design: We investigated the interactive mechanisms between Tregs and oral cancer cells in regulating sterol regulatory element-binding protein 1 (SREBP1)/ kallikrein-related peptidase 8 (KLK8)/ CC motif chemokine ligand 22 (CCL22) axis by GB treatment., Methods: Tissue array staining and the gene expression omnibus (GEO) database were used to identify the correlation between SREBP1/ KLK8/ CCL22 in oral cancer prognosis. The molecular effects of GB on SAS, KYSE-510, and TE-1 cells were examined by RNA sequencing. Electrophoretic mobility shift assay was used to analyse SREBF1/KLK8 transcription promoter activity. SREBP1 and KLK8 genetic engineering or recombinant proteins were used to evaluate CCL22 expression and Treg chemotactic response. An MOC-2-implanted mouse model was used to evaluate the therapeutic effects of GB and genetic engineering conditions., Results: Web-based visualization platform and tissue array data showed that SREBP1 expression was negatively correlated with oral cancer prognosis and SREBP1 and KLK8 positively correlated (R = 0.4648, p < 0.001). In addition, in vivo, ex vivo and in vitro experiments demonstrated that GB treatment or SREBP1 knockdown inhibited cancer cells proliferation, migration and Tregs chemotaxis. Mechanistically, GB treatment or SREBP1 knockdown attenuated SREBP1-regulated transcription of KLK8, reducing CCL22 secretion. Conversely, treatment with U18666a or SREBP1 transfection reversed these effects., Conclusions: GB is a novel SREBP1 inhibitor that effectively prevents immune escape by oral cancer cells through modulation of the SREBP1/KLK8/CCL22 axis, presenting a promising new approach for oral cancer immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Chemokines are small proteins involved in recruiting leukocytes to sites of inflammation via interactions with specific cell surface receptors. CCL22 is a chemokine known to play a critical role in inflammatory diseases such as atopic dermatitis and asthma; inhibition of this chemokine therefore represents an attractive therapeutic strategy. Herein, we describe the discovery of cyclic d-sulfopeptide inhibitors of CCL22 identified through mirror-image mRNA display with genetic reprogramming. Chemical synthesis of mirror-image d-CCL22 enabled screening of a cyclic peptide library comprised of all l-amino acids, with reprogramming of l-sulfotyrosine to mimic the presence of this post-translational modification on native chemokine receptors. Enriched macrocyclic peptides were prepared in their mirror-image d-form and assessed for binding against native l-CCL22. The most potent ligand, a plasma-stable d-cyclic peptide bearing four d-sulfotyrosine residues, exhibited nanomolar affinity for CCL22, high selectivity over other chemokines, and nanomolar inhibition of CCL22 signaling through CCR4. This work highlights the vast potential of mirror-image mRNA display technology for discovering proteolytically stable d-peptide inhibitors of protein-protein interactions relevant across a range of therapeutic indications.

Over 75% of patients with ovarian cancer present with late-stage disease, often accompanied by extensive metastasis. The metastatic cascade is driven by a sub-population of transcriptionally plastic cells known as "leader cells" (LCs), which play a critical role in collective invasion yet remain poorly understood. LCs are marked by the expression of keratin-14 (KRT14), which determines their migratory and invasive capacity in ovarian cancer. This study demonstrates that KRT14+ LCs promote tumor progression through immunosuppression and immune privilege in vivo. In the ID8 syngeneic epithelial ovarian cancer mouse model, tumor-specific loss of KRT14+ LCs impairs tumor progression and metastatic spread without affecting cellular proliferation. Immune profiling shows reduced immunosuppressive regulatory T cells (Tregs) and M2 macrophages and improved CD8 + T cell/Treg ratios in LC knockout (LC KO ) mice. Conversely, forced LC overexpression accelerates metastasis and increases the secretion of immunosuppressive chemokines, such as CCL22 and CCL5, highlighting the role of KRT14+ LCs in immune suppression and metastatic progression., Competing Interests: Declaration of interests The authors declare no competing interests., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

Backgrounds: Severe asthma is a significant health burden because children with severe asthma are vulnerable to medication-related side effects, life-threatening deterioration, and impaired quality of life. However, there is a lack of data to elucidate the role of inflammatory variables in asthma. This study aimed to compare the levels of inflammatory factors in serum and sputum in children with acute and stable asthma to those in healthy children and the ability to predict clinical response to azithromycin therapy., Methods: This study recruited 95 individuals aged 1-3 years old and collected data from January 2018 to 2020. We examined serum and sputum inflammatory factors and constructed the least absolute shrinkage and selection operator (LASSO) model. Predictive models were constructed through multifactor logistic regression and presented in the form of column-line plots. The performance of the column-line diagrams was measured by subject work characteristics (ROC) curves, calibration plots, and decision curve analysis (DCA). Then, filter-paper samples were collected from 45 children with acute asthma who were randomly assigned to receive either azithromycin (10 mg/kg, n = 22) or placebo (n = 23). Pretreatment levels of immune mediators were then analyzed and compared with clinical response to azithromycin therapy., Results: Of the 95 eligible participants, 21 (22.11%) were healthy controls, 29 (30.53%) had stable asthma, and 45 (47.37%) had acute asthma. The levels of interferon-γ (IFN-γ), tumor necrosis factor-a (TNF-α), chemokine CCL22 (CCL22), interleukin 12 (IL-12), chemokine CCL4 (CCL4), chemokine CCL2 (CCL2), and chemokine CCL13 (CCL13）were significantly higher in the acute asthma group than in the stable asthma group. A logistic regression analysis was performed using CCL22 and IL-1 as independent variables. Additionally, IFN-γ, TNF-α, IL-1, IL-13, and CCL22 were identified in the LASSO model. Finally, we found that CCL22 and IL-1 were more responsive in predicting the response to azithromycin treatment., Conclusion: Our results show that CCL22 and IL-1 are both representative markers during asthma symptom exacerbations and an immune mediator that can predict response to azithromycin therapy., (© 2024 The Author(s). Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Dendritic cells (DCs) are crucial for initiating protective immune responses and have also been implicated in the generation and regulation of Foxp3 + regulatory T cells (Treg cells). Here, we show that in the lamina propria of the small intestine, the alternative NF-κB family member RelB is necessary for the differentiation of cryptopatch and isolated lymphoid follicle-associated DCs (CIA-DCs). Moreover, single-cell RNA sequencing reveals a RelB-dependent signature in migratory DCs in mesenteric lymph nodes favoring DC-Treg cell interaction including elevated expression and release of the chemokine CCL22 from RelB-deficient conventional DCs (cDCs). In line with the key role of CCL22 to facilitate DC-Treg cell interaction, RelB-deficient DCs have a selective advantage to interact with Treg cells in an antigen-specific manner. In addition, DC-specific RelB knockout animals show increased total Foxp3 + Treg cell numbers irrespective of inflammatory status. Consequently, DC-specific RelB knockout animals fail to mount protective Th2-dominated immune responses in the intestine after infection with Heligmosomoides polygyrus bakeri. Thus, RelB expression in cDCs acts as a rheostat to establish a tolerogenic set point that is maintained even during strong type 2 immune conditions and thereby is a key regulator of intestinal homeostasis., (© 2024. The Author(s).)

Aims: Acute lymphoblastic leukemia (ALL) is the most common type of pediatrics cancer. Chemokines exert different roles in leukemia process through leukocyte recruitment and regulation of disease severity. Due to the prominent roles of chemokine/receptor axes, this study aimed to measure the blood expression levels of CCR4 and their ligands in pediatrics with B-cell ALL (B-ALL). We also evaluated the impact of cytotoxic chemotherapy on this axis., Material and Method: Thirty children suffering from B-ALL were included in the study and followed up for 30 days after completion of a chemotherapy course. The blood sampling was performed before and after chemotherapy. 30 healthy donors have also entered the study as control subjects. The mRNA expression of CCL17, CCL22 and CCR4 genes was determined by quantitative real-time PCR. The frequency of the peripheral blood mononuclear cells expressing CCR4 (CCR4 + PBMCs) was also evaluated by the flow cytometry method. Moreover, we evaluated the association of the CCL17/CCL22-CCR4 axis with some diagnostic, prognostic and predictive biomarkers in ALL patients., Results: There was overexpression of the CCL17/CCL22-CCR4 axis along with lactate dehydrogenase (LDH) in pediatrics with B-ALL compared to healthy controls. After induction of chemotherapy, the blood expression levels of the CCL17/CCL22-CCR4 axis have reached the levels of healthy controls. The findings for the blood expression levels of CCR4 were also confirmed using flow cytometry., Conclusion: The CCL17/CCL22-CCR4 axis can be used as a novel predictive and prognostic biomarker in B-ALL., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: Radiation-mediated immune suppression limits efficacy and is a barrier in cancer therapy. Radiation induces negative regulators of tumor immunity including regulatory T cells (Treg). Mechanisms underlying Treg infiltration after radiotherapy (RT) are poorly defined. Given that conventional dendritic cells (cDC) maintain Treg, we sought to identify and target cDC signaling to block Treg infiltration after radiation., Experimental Design: Transcriptomics and high dimensional flow cytometry revealed changes in murine tumor cDC that not only mediate Treg infiltration after RT but also associate with worse survival in human cancer datasets. Antibodies perturbing a cDC-CCL22-Treg axis were tested in syngeneic murine tumors. A prototype interferon-anti-epidermal growth factor receptor fusion protein (αEGFR-IFNα) was examined to block Treg infiltration and promote a CD8+ T cell response after RT., Results: Radiation expands a population of mature cDC1 enriched in immunoregulatory markers that mediates Treg infiltration via the Treg-recruiting chemokine CCL22. Blocking CCL22 or Treg depletion both enhanced RT efficacy. αEGFR-IFNα blocked cDC1 CCL22 production while simultaneously inducing an antitumor CD8+ T cell response to enhance RT efficacy in multiple EGFR-expressing murine tumor models, including following systemic administration., Conclusions: We identify a previously unappreciated cDC mechanism mediating Treg tumor infiltration after RT. Our findings suggest blocking the cDC1-CCL22-Treg axis augments RT efficacy. αEGFR-IFNα added to RT provided robust antitumor responses better than systemic free interferon administration and may overcome clinical limitations to interferon therapy. Our findings highlight the complex behavior of cDC after RT and provide novel therapeutic strategies for overcoming RT-driven immunosuppression to improve RT efficacy. See related commentary by Kalinski et al., p. 4260., (©2024 American Association for Cancer Research.)

Objective: To study the expressions of C-C class chemokine 17 (CCL17), C-C class chemokine 22 (CCL22), and C-C chemokine receptor 4 (CCR4) in newly diagnosed multiple myeloma (NDMM) for analyzing their correlations with clinical features and to preliminarily explore their roles in the development of NDMM. Methods: The study included 40 patients with NDMM and 20 healthy volunteers from the Department of Hematology of the Affiliated Hospital of Zunyi Medical University from July 2020 to December 2022. Peripheral blood, bone marrow, and bone marrow biopsy tissue samples were collected from the two groups. The expression levels of CCL17, CCL22, and CCR4 in patients with NDMM were analyzed using real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry. The mRNA expression levels of CCL17, CCL22, and CCR4 in the bone marrow mononuclear cell (BMMNC) of patients with NDMM were analyzed to assess their correlations with clinical indicators. Results: The mRNA expression levels of CCL17, CCL22, and CCR4 in BMMNC were higher in patients with NDMM than in controls (all P <0.05). The protein expression levels of CCL17 and CCL22 in peripheral blood supernatants and bone marrow supernatants were higher in patients with NDMM than in controls (all P <0.05). The expression levels of CCL17, CCL22, and CCR4 in bone marrow biopsy tissues were higher in patients with NDMM than in controls (all P <0.05). The mRNA expression level of CCL17 was increased in NDMM patients with combined anemia, bone damage, renal damage, and M protein level ≥30 g/L (all P <0.05). The mRNA expression level of CCL22 was increased in NDMM patients with combined anemia, bone damage, and renal damage (all P <0.05). The mRNA expression level of CCR4 was increased in NDMM patients with combined anemia and renal damage (all P <0.05) . Conclusion: CCL17, CCL22, and CCR4 were highly expressed in clinical samples from patients with NDMM compared to those from controls, and they may be involved in the occurrence and development of NDMM.

The efficacy of adoptive T cell therapy (ACT) for the treatment of solid tumors remains challenging. In addition to the poor infiltration of effector T (Teff) cells limited by the physical barrier surrounding the solid tumor, another major obstacle is the extensive infiltration of regulatory T (Treg) cells, a major immunosuppressive immune cell subset, in the tumor microenvironment. Here, this work develops a grooved microneedle patch for augmenting ACT, aiming to simultaneously overcome physical and immunosuppressive barriers. The microneedles are engineered through an ice-templated method to generate the grooved structure for sufficient T-cell loading. In addition, with the surface modification of chemokine CCL22, the MNs could not only directly deliver tumor-specific T cells into solid tumors through physical penetration, but also specifically divert Treg cells from the tumor microenvironment to the surface of the microneedles via a cytokine concentration gradient, leading to an increase in the ratio of Teff cells/Treg cells in a mouse melanoma model. Consequently, this local delivery strategy of both T cell receptor T cells and chimeric antigen receptor T cells via the CCL22-modified grooved microneedles as a local niche could significantly enhance the antitumor efficacy and reduce the on-target off-tumor toxicity of ACT., (© 2024 Wiley‐VCH GmbH.)

There is a regional preference around lymph nodes (LNs) for adipose beiging. Here, we show that local LN removal within inguinal white adipose tissue (iWAT) greatly impairs cold-induced beiging, and this impairment can be restored by injecting M2 macrophages or macrophage-derived C-C motif chemokine (CCL22) into iWAT. CCL22 injection into iWAT effectively promotes iWAT beiging, while blocking CCL22 with antibodies can prevent it. Mechanistically, the CCL22 receptor, C-C motif chemokine receptor 4 (CCR4), within eosinophils and its downstream focal adhesion kinase/p65/interleukin-4 signaling are essential for CCL22-mediated beige adipocyte formation. Moreover, CCL22 levels are inversely correlated with body weight and fat mass in mice and humans. Acute elevation of CCL22 levels effectively prevents diet-induced body weight and fat gain by enhancing adipose beiging. Together, our data identify the CCL22-CCR4 axis as an essential mediator for LN-controlled adaptive thermogenesis and highlight its potential to combat obesity and its associated complications.

Long non-coding RNA (lncRNA) LINC00472 has a close connection with the development of tumors. The aim was to explore the role of LINC00472 on NSCLC cell biological function in vivo and its potential mechanisms. The mRNA levels of LncRNA 00472 and microRNA-23a-3p, were determined by RT-qPCR. Cell Counting Kit-8, cell scratches and western blot assays were used to analyze the proliferation, migration and level of apoptosis-associated proteins. Luciferase reporter assay validates the binding between LINC00472/CCL22 and miR-23a-3p. LINC00472 and CCL22 were lowly expressed in NSCLC tissues and cells, while miR-23a-3p expression was upregulated. LINC00472 overexpression significantly depressed NSCLC cell cellular behavior, whereas promoting cell death. MiR-23a-3p could reverse these above-mentioned biological behavior changes caused by LINC00472 overexpression. Additionally, LINC00472 increased CCL22 expression through sponging miR-23a-3p. Knocking down CCL22 antagonized the inhibitory effect of LINC00472 on NSCLC cell survival. LINC00472 may reduce the cellular growth, and accelerate death of NSCLC through increasing CCL22 expression by targeting miR-23a-3p.

CCL22 is a macrophage-derived immunosuppressive chemokine that recruits regulatory T cells through the CCL22:CCR4 axis, playing an important role in homeostatic and inflammatory responses. A CCL22-overexpressing human induced pluripotent stem cell line (CNNDi001-A-2) was generated by lentiviral transduction to further study the function of CCL22. The cell line was confirmed to have normal proliferation and pluripotency and could be further differentiated into islet cells for cell replacement therapy in diabetes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Double-stranded DNA (dsDNA) in the cytoplasm of eukaryotic cells is abnormal and typically indicates the presence of pathogens or mislocalized self-DNA. Multiple sensors detect cytosolic dsDNA and trigger robust immune responses via activation of type I interferons. Several cancer immunotherapy treatments also activate cytosolic nucleic acid sensing pathways, including oncolytic viruses, nucleic acid-based cancer vaccines, and pharmacological agonists. We report here that cytosolic dsDNA introduced into malignant cells can robustly upregulate expression of CCL22, a chemokine responsible for the recruitment of regulatory T cells (Tregs). Tregs in the tumor microenvironment are thought to repress anti-tumor immune responses and contribute to tumor immune evasion. Surprisingly, we found that CCL22 upregulation by dsDNA was mediated primarily by interferon regulatory factor 3 (IRF3), a key transcription factor that activates type I interferons. This finding was unexpected given previous reports that type I interferon alpha (IFN-α) inhibits CCL22 and that IRF3 is associated with strong anti-tumor immune responses, not Treg recruitment. We also found that CCL22 upregulation by dsDNA occurred concurrently with type I interferon beta (IFN-β) upregulation. IRF3 is one of two transcription factors downstream of the STimulator of INterferon Genes (STING), a hub adaptor protein through which multiple dsDNA sensors transmit their signals. The other transcription factor downstream of STING, NF-κB, has been reported to regulate CCL22 expression in other contexts, and NF-κB has also been associated with multiple pro-tumor functions, including Treg recruitment. However, we found that NF-κB in the context of activation by cytosolic dsDNA contributed minimally to CCL22 upregulation compared with IRF3. Lastly, we observed that two strains of the same cell line differed profoundly in their capacity to upregulate CCL22 and IFN-β in response to dsDNA, despite apparent STING activation in both cell lines. This finding suggests that during tumor evolution, cells can acquire, or lose, the ability to upregulate CCL22. This study adds to our understanding of factors that may modulate immune activation in response to cytosolic DNA and has implications for immunotherapy strategies that activate DNA sensing pathways in cancer cells., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: An increasing infiltration of FoxP3-positive T-regs is associated with a higher grade of cervical intraepithelial neoplasia. The T-reg-recruiting chemokine CCL22 is expressed in various tumour entities. Aim of our study was to investigate the role of CCL22 in the progression and regression of cervical intraepithelial neoplasias, especially in patients with intermediate cervical intraepithelial neoplasias (CIN II). Furthermore, our aim was to characterize the CCL22-producing cells and explore the role of innate immunity in the process of cells recruitment., Methods: CCL22 expression was analyzed immunohistochemically in 169 patient samples. The immunoreactive score as well as the median numbers of positive cells were calculated in each slide and correlated with the histological CIN grade and FoxP3 expression. Additionally, CD68/CCL22 as well as CD68/PPARγ and CD68/FoxP3 expression were examined by double immunofluorescence. Statistical analysis was performed by SPSS 26., Results: A significantly higher expression of epithelial CCL22 in CIN II with progression in comparison to CIN II with regression (p = 0.006) could be detected. CCL22 was correlated with FoxP3 (Spearman's Rho: 0.308; p < 0.01). In 88%, CCL22-positive cells were positive for CD68, and 71% of CD68-positive macrophages expressed PPARγ. Colocalization of CD68 and FoxP3 was detected in 12%., Conclusion: We could demonstrate that increased expression of CCL22, mainly produced by macrophages, correlates with elevated potential of malignancy. CCL22 expression could act as a predictor for regression and progression in cervical intraepithelial neoplasia, and it may help in the decision process regarding surgical treatment versus watchful waiting strategy in order to prevent conisation-associated risks. Furthermore, our findings support the potential of CCL22-producing cells as a target for immune therapy in cervical cancer patients., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The main pathogenic factor in atopic dermatitis (AD) is Th2 inflammation, and levels of serum CCL17 and CCL22 are related to severity in AD patients. Fulvic acid (FA) is a kind of natural humic acid with anti-inflammatory, antibacterial, and immunomodulatory effects. Our experiments demonstrated the therapeutic effect of FA on AD mice and revealed some potential mechanisms. FA was shown to reduce TARC/CCL17 and MDC/CCL22 expression in HaCaT cells stimulated by TNF-α and IFN-γ. The inhibitors showed that FA inhibits CCL17 and CCL22 production by deactivating the p38 MAPK and JNK pathways. After 2,4-dinitrochlorobenzene (DNCB) induction in mice with atopic dermatitis, FA effectively reduced the symptoms and serum levels of CCL17 and CCL22. In conclusion, topical FA attenuated AD via downregulation of CCL17 and CCL22, via inhibition of P38 MAPK and JNK phosphorylation, and FA is a potential therapeutic agent for AD.

Background: Macrophages are an important component of the tumour immune microenvironment (TME) and can promote tumour growth and metastasis. Macrophage-secreted chemokine-ligand-23 (CCL23) induces ovarian cancer cell migration via chemokine-receptor 1 (CCR1). However, the effect of CCL23 on other immune cells in the TME is unknown., Methods: CCL23 levels were measured by ELISA. The expression of surface markers in exhaustion assays was quantified by flow cytometry. Signalling pathways were identified by phosphokinase array and validated by western blot., Results: Ascites from patients with high-grade serous ovarian cancer (HGSC) contain high levels of CCL23. Similarly, significantly higher CCL23 levels were found in plasma from HGSC patients compared to healthy individuals. RNA-seq analysis of ovarian cancer tissues from TCGA showed that expression of CCL23 correlated with the presence of macrophages. In tissues with high levels of CCL23 and macrophage content, the fraction of CD8 + T cells expressing exhaustion markers CTLA-4 and PD-1 were significantly higher compared to low-level CCL23 tissues. In vitro, CCL23 induced upregulation of immune checkpoint proteins on CD8 + T cells, including CTLA-4, TIGIT, TIM-3 and LAG-3 via phosphorylation of GSK3β in CD8 + T cells., Conclusions: Our data suggest that CCL23 produced by macrophages contributes to the immune-suppressive TME in ovarian cancer by inducing an exhausted T-cell phenotype., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Tumor cell dependence on activated oncogenes is considered a therapeutic target, but protumorigenic microenvironment-mediated cellular addiction to specific oncogenic signaling molecules remains to be further defined. Here, we showed that tumor-associated macrophages (TAMs) produced an abundance of C-C motif chemokine 22 (CCL22), whose expression in the tumor stroma was positively associated with the level of intratumoral phospho-focal adhesion kinase (pFAK Tyr 397 ), tumor metastasis and reduced patient survival. Functionally, CCL22-stimulated hyperactivation of FAK was correlated with increased malignant progression of cancer cells. CCL22-induced addiction to FAK was demonstrated by the persistent suppression of tumor progression upon FAK-specific inhibition. Mechanistically, we identified that diacylglycerol kinase α (DGKα) acted as a signaling adaptor to link the CCL22 receptor C-C motif chemokine receptor 4 (CCR4) and FAK and promoted CCL22-induced activation of the FAK/AKT pathway. CCL22/CCR4 signaling activated the intracellular Ca 2+ /phospholipase C-γ1 (PLC-γ1) axis to stimulate the phosphorylation of DGKα at a tyrosine residue (Tyr 335 ) and promoted the translocation of DGKα to the plasma membrane to assemble the DGKα/FAK signalosome, which critically contributed to regulating sensitivity to FAK inhibitors in cancer cells. The identification of TAM-driven intratumoral FAK addiction provides opportunities for utilizing the tumor-promoting microenvironment to achieve striking anticancer effects., (© 2022. The Author(s).)

Polysiphonia morrowii is a well-known red alga that has promising pharmacological characteristics. The current study evaluates the protective effect of 3-bromo-4,5-dihydroxybenzaldehyde (BDB) isolated from P. morrowii on tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated inflammation and skin barrier deterioration in HaCaT keratinocytes. The anti-inflammatory effect of BDB in TNF-α/IFN-γ-stimulated HaCaT keratinocytes is evaluated by investigating nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, inflammatory cytokines, and chemokines. Further, the interaction between BDB and the skin barrier functions in stimulated HaCaT keratinocytes is investigated. The findings of the study reveal that BDB dose-dependently increases cell viability while decreasing intracellular reactive oxygen species (ROS) production. BDB downregulates the expression of inflammatory cytokines, interleukin (IL)-6, -8, -13, IFN-γ, TNF-α, and chemokines, Eotaxin, macrophage-derived chemokine (MDC), regulated on activation, normal T cells expressed and secreted (RANTES), and thymus and activation-regulated chemokine (TARC) by modulating the MAPK and NF-κB signaling pathways in TNF-α/IFN-γ-stimulated HaCaT keratinocytes. Furthermore, BDB increases the production of skin hydration proteins and tight junction proteins in stimulated HaCaT keratinocytes by preserving skin moisturization and tight junction stability. These findings imply that BDB exhibits a protective ability against inflammation and deterioration of skin barrier via suppressing the expression of inflammatory signaling in TNF-α/IFN-γ-stimulated HaCaT keratinocytes.

Long noncoding RNA (LncRNA) is a new type of regulatory RNA. LncRNA HOX antisense intergenic RNA (HOTAIR), as an oncogene in non-small cell lung cancer (NSCLC), is one of the key determinants of tumor progression. However, its possible molecular mechanism and the immunomodulatory pathway involved in NSCLC are still unclear. This study aims to explore whether HOTAIR promotes proliferation, migration and invasion of the NSCLC cells by inhibiting the expression of C-C Motif Chemokine Ligand 22 (CCL22). We collected 30 clinical samples of cancer and adjacent normal tissues from the patients with NSCLC, using real-time quantitative polymerase chain reaction (RT-qPCR) to detect the LncRNA HOTAIR and CCL22 mRNA expression in tissues. Immunohistochemistry was used to detect the protein expression of CCL22 in cancer and adjacent normal tissues. Cell experiments were conducted to verify that LncRNA HOTAIR regulates the expression of CCL22 and participates in the progress of NSCLC. The antisense oligonucleotide (ASO) probe interfering with LncRNA HOTAIR and the interference fragment of CCL22 (si-CCL22) were constructed. A549 cells were co-transfected with ASO-HOTAIR and si-CCL22. We used RT-qPCR to detect the expression of LncRNA HOTAIR and CCL22 mRNA in the cells, enzyme-linked immunosorbent assay (ELISA) used to detect the CCL22 protein level in the cell supernatant. 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay was applied to detect cell proliferation, the Flow cytometry to detect cell apoptosis. Finally, the Transwell test was utilized to detect cell migration and invasion. In conclusion, this study suggests that HOTAIR may promote proliferation, migration and invasion of the NSCLC cells by inhibiting CCL22 expression, which may play a key role in NSCLC cell immunity., Competing Interests: NO authors have competing interests.

There are several open questions to be answered regarding the pathophysiology of the development of preeclampsia (PE). Numerous factors are involved in its genesis, such as defective placentation, vascular impairment, and an altered immune response. The activation of the adaptive and innate immune system represents an immunologic, particularity during PE. Proinflammatory cytokines are predominantly produced, whereas immune regulatory and immune suppressive factors are diminished in PE. In the present study, we focused on the recruitment of regulatory T cells (Tregs) which are key players in processes mediating immune tolerance. To identify Tregs in the decidua, an immunohistochemical staining of FoxP3 of 32 PE and 34 control placentas was performed. A clearly reduced number of FoxP3-positive cells in the decidua of preeclamptic women could be shown in our analysis ( p = 0.036). Furthermore, CCL22, a well-known Treg chemoattractant, was immunohistochemically evaluated. Interestingly, CCL22 expression was increased at the maternal-fetal interface in PE-affected pregnancies ( p syncytiotrophoblas t = 0.035, p decidu a = 0.004). Therefore, the hypothesis that Tregs undergo apoptosis at the materno-fetal interface during PE was generated, and verified by FoxP3/TUNEL (TdT-mediated dUTP-biotin nick end labeling) staining. Galectin-2 (Gal-2), a member of the family of carbohydrate-binding proteins, which is known to be downregulated during PE, seems to play a pivotal role in T cell apoptosis. By performing a cell culture experiment with isolated Tregs, we could identify Gal-2 as a factor that seems to prevent the apoptosis of Tregs. Our findings point to a cascade of apoptosis of Tregs at the materno-fetal interface during PE. Gal-2 might be a potential therapeutic target in PE to regulate immune tolerance.

Recently, cytokine-induced killer (CIK) cells have been shown to possess effective cytotoxic activity against some tumor cells both in vitro and in clinical research. Furthermore, dendritic cell-activated CIK (DC-CIK) cells display significantly increased antitumor activity compared to unstimulated CIK cells. Study findings indicate DC cells can secrete chemokine C-C motif ligand 17 (CCL17) and chemokine C-C motif ligand 22 (CCL22) with a common receptor molecule, C-C chemokine receptor type-4(CCR4). CCL17 and CCL22 levels were measured by ELISA from CIK cell culture supernatants and the expression of CCR4 on CIK and DC-CIK cells was analyzed by flow cytometry. Through Migration and Killing assays, further analyzed the effects of the altered expression levels of CCR4 on the chemotactic ability and the tumor-killing efficiency of CIK cells. We found markedly increased CCL17 and CCL22 in supernatants of DC-CIK co-cultures. Similarly, the expression of CCR4 was also increased on CIK cells in these co-cultures. Further, the stimulation of CCL17 and CCL22 increased expression of the CCR4 and enhanced the migratory capacity and antitumor efficacy of CIK cells. Simultaneously, similar effects had achieved by transfecting the CCR4 gene into CIK cells. DC cells may promote the expression of CCR4 on CIK cells by secreting CCL17 and CCL22, thereby promoting infiltration of DC-CIK cells into the tumor microenvironment, and exerting stronger antitumor activity than CIK cells., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Inflammatory pain, such as hypersensitivity resulting from surgical tissue injury, occurs as a result of interactions between the immune and nervous systems with the orchestrated recruitment and activation of tissue-resident and circulating immune cells to the site of injury. Our previous studies identified a central role for Ly6C low myeloid cells in the pathogenesis of postoperative pain. We now show that the chemokines CCL17 and CCL22, with their cognate receptor CCR4, are key mediators of this response. Both chemokines are up-regulated early after tissue injury by skin-resident dendritic and Langerhans cells to act on peripheral sensory neurons that express CCR4. CCL22, and to a lesser extent CCL17, elicit acute mechanical and thermal hypersensitivity when administered subcutaneously; this response abrogated by pharmacological blockade or genetic silencing of CCR4. Electrophysiological assessment of dissociated sensory neurons from naïve and postoperative mice showed that CCL22 was able to directly activate neurons and enhance their excitability after injury. These responses were blocked using C 021 and small interfering RNA (siRNA)-targeting CCR4. Finally, our data show that acute postoperative pain is significantly reduced in mice lacking CCR4, wild-type animals treated with CCR4 antagonist/siRNA, as well as transgenic mice depleted of dendritic cells. Together, these results suggest an essential role for the peripheral CCL17/22:CCR4 axis in the genesis of inflammatory pain via direct communication between skin-resident dendritic cells and sensory neurons, opening therapeutic avenues for its control., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Toxoplasma gondii is an intracellular protozoan pathogen of humans that can cross the placenta and result in adverse pregnancy outcomes and long-term birth defects. The mechanisms used by T. gondii to cross the placenta are unknown, but complex interactions with the host immune response are likely to play a role in dictating infection outcomes during pregnancy. Prior work showed that T. gondii infection dramatically and specifically increases the secretion of the immunomodulatory chemokine CCL22 in human placental cells during infection. Given the important role of this chemokine during pregnancy, we hypothesized that CCL22 induction was driven by a specific T. gondii-secreted effector. Using a combination of bioinformatics and molecular genetics, we have now identified T. gondii GRA28 as the gene product required for CCL22 induction. GRA28 is secreted into the host cell, where it localizes to the nucleus, and deletion of the GRA28 gene results in reduced CCL22 placental cells as well as a human monocyte cell line. The impact of GRA28 on CCL22 production is also conserved in mouse immune and placental cells both in vitro and in vivo . Moreover, parasites lacking GRA28 are impaired in their ability to disseminate throughout the animal, suggesting a link between CCL22 induction and the ability of the parasite to cause disease. Overall, these data demonstrate a clear function for GRA28 in altering the immunomodulatory landscape during infection of both placental and peripheral immune cells and show a clear impact of this immunomodulation on infection outcome. IMPORTANCE Toxoplasma gondii is a globally ubiquitous pathogen that can cause severe disease in HIV/AIDS patients and can also cross the placenta and infect the developing fetus. We have found that placental and immune cells infected with T. gondii secrete significant amounts of a chemokine (called CCL22) that is critical for immune tolerance during pregnancy. In order to better understand whether this is a response by the host or a process that is driven by the parasite, we have identified a T. gondii gene that is absolutely required to induce CCL22 production in human cells, indicating that CCL22 production is a process driven almost entirely by the parasite rather than the host. Consistent with its role in immune tolerance, we also found that T. gondii parasites lacking this gene are less able to proliferate and disseminate throughout the host. Taken together, these data illustrate a direct relationship between CCL22 levels in the infected host and a key parasite effector and provide an interesting example of how T. gondii can directly modulate host signaling pathways in order to facilitate its growth and dissemination.

A great many microRNAs (miRNAs) have been reported to play different roles in human cancers, including gastric cancer (GC). However, the specific character of miR-23a-3p in GC has not been elucidated. This study was to explore the function of miR-23a-3p in GC. The results manifested that miR-23a-3p was down-regulated in GC and patients with reduced miR-23a-3p had poor prognosis. Functional experiments assured that elevated miR-23a-3p refrained GC proliferation, invasion, migration, PIK3/Akt phosphorylation and apoptosis, while knockdown miR-23a-3p accelerated the growth of GC. Double luciferase report experiments manifested that miR-23a-3p targeted CCL22 expression. Functional rescue experiments affirmed that the repression of elevated miR-23a-3p on GC was reversed by simultaneous augmented CCL22. In vivo , elevated miR-23a-3p restrained the volume and tumor of GC and reduced the expression of CCL22 and phosphorylated PIK3/Akt, while knockdown miR-23a-3p motivated tumor growth. In conclusion, the results of this study indicate that miR-23a-3p plays a repressive role in GC, and affects the progression of GC via down-regulating CCL22 and blocking PI3K/AKT signal transduction pathway, which may offer a new molecular target for clinical treatment of GC.

Background: In Mali, cutaneous leishmaniasis (CL) and filariasis are co-endemic. Previous studies in animal models of infection have shown that sand fly saliva enhance infectivity of Leishmania parasites in naïve hosts while saliva-specific adaptive immune responses may protect against cutaneous and visceral leishmaniasis. In contrast, the human immune response to Phlebotomus duboscqi (Pd) saliva, the principal sand fly vector in Mali, was found to be dichotomously polarized with some individuals having a Th1-dominated response and others having a Th2-biased response. We hypothesized that co-infection with filarial parasites may be an underlying factor that modulates the immune response to Pd saliva in endemic regions., Methodology/principal Findings: To understand which cell types may be responsible for polarizing human responses to sand fly saliva, we investigated the effect of salivary glands (SG) of Pd on human monocytes. To this end, elutriated monocytes were cultured in vitro, alone, or with SG, microfilariae antigen (MF ag) of Brugia malayi, or LPS, a positive control. The mRNA expression of genes involved in inflammatory or regulatory responses was then measured as were cytokines and chemokines associated with these responses. Monocytes of individuals who were not exposed to sand fly bites (mainly North American controls) significantly upregulated the production of IL-6 and CCL4; cytokines that enhance leishmania parasite establishment, in response to SG from Pd or other vector species. This selective inflammatory response was lost in individuals that were exposed to sand fly bites which was not changed by co-infection with filarial parasites. Furthermore, infection with filarial parasites resulted in upregulation of CCL22, a type-2 associated chemokine, both at the mRNA levels and by its observed effect on the frequency of recruited monocytes., Conclusions/significance: Together, our data suggest that SG or recombinant salivary proteins from Pd alter human monocyte function by upregulating selective inflammatory cytokines., Competing Interests: The authors have declared that no competing interests exist.

Antibody affinity maturation depends on positive selection in germinal centres (GCs) of rare B cell clones that acquire higher-affinity B cell receptors via somatic hypermutation, present more antigen to follicular helper T (T FH ) cells and, consequently, receive more contact-dependent T cell help 1 . As these GC B cells and T FH cells do not maintain long-lasting contacts in the chaotic GC environment 2-4 , it is unclear how sufficient T cell help is cumulatively focused onto those rare clones. Here we show that, upon stimulation of CD40, GC B cells upregulate the chemokine CCL22 and to a lesser extent CCL17. By engaging the chemokine receptor CCR4 on T FH cells, CCL22 and CCL17 can attract multiple helper cells from a distance, thus increasing the chance of productive help. During a GC response, B cells that acquire higher antigen-binding affinities express higher levels of CCL22, which in turn 'highlight' these high-affinity GC B cells. Acute increase or blockade of T FH cells helps to rapidly increase or decrease CCL22 expression by GC B cells, respectively. Therefore, a chemokine-based intercellular reaction circuit links the amount of T cell help that individual B cells have received recently to their subsequent ability to attract more help. When CCL22 and CCL17 are ablated in B cells, GCs form but B cells are not affinity-matured efficiently. When competing with wild-type B cells in the same reaction, B cells lacking CCL22 and CCL17 receive less T cell help to maintain GC participation or develop into bone-marrow plasma cells. By uncovering a chemokine-mediated mechanism that highlights affinity-improved B cells for preferential help from T FH cells, our study reveals a principle of spatiotemporal orchestration of GC positive selection.

The interplay of type-2 inflammation and antiviral immunity underpins asthma exacerbation pathogenesis. Virus infection induces type-2 inflammation-promoting chemokines CCL17 and CCL22 in asthma; however, mechanisms regulating induction are poorly understood. By using a human rhinovirus (RV) challenge model in human airway epithelial cells in vitro and mice in vivo, we assessed mechanisms regulating CCL17 and CCL22 expression. Subjects with mild to moderate asthma and healthy volunteers were experimentally infected with RV and airway CCL17 and CCL22 protein quantified. In vitro airway epithelial cell- and mouse-RV infection models were then used to define STAT6- and NF-κB-mediated regulation of CCL17 and CCL22 expression. Following RV infection, CCL17 and CCL22 expression was higher in asthma, which differentially correlated with clinical and immunological parameters. Air-liquid interface-differentiated primary epithelial cells from donors with asthma also expressed higher levels of RV-induced CCL22. RV infection boosted type-2 cytokine-induced STAT6 activation. In epithelial cells, type-2 cytokines and STAT6 activation had differential effects on chemokine expression, increasing CCL17 and suppressing CCL22, whereas NF-κB promoted expression of both chemokines. In mice, RV infection activated pulmonary STAT6, which was required for CCL17 but not CCL22 expression. STAT6-knockout mice infected with RV expressed increased levels of NF-κB-regulated chemokines, which was associated with rapid viral clearance. Therefore, RV-induced upregulation of CCL17 and CCL22 was mediated by NF-κB activation, whereas expression was differentially regulated by STAT6. Together, these findings suggest that therapeutic targeting of type-2 STAT6 activation alone will not block all inflammatory pathways during RV infection in asthma.

Atypical chemokine receptors (ACKRs) have emerged as important regulators or scavengers of homeostatic and inflammatory chemokines. Among these atypical receptors, ACKR4 is reported to bind the homeostatic chemokines CCL19, CCL21, CCL25 and CXCL13. In a recent study by Matti et al., the authors show that ACKR4 is also a receptor for CCL20, previously established to bind to CCR6 only. They provide convincing evidence that, just as for its other chemokine ligands, ACKR4 rapidly internalizes CCL20 both in vitro and in vivo. Independently of this discovery, we undertook a screening program aiming at reassessing the activity of the 43 human chemokines toward ACKR4 using a highly sensitive β-arrestin recruitment assay. This systematic analysis confirmed CCL20 as a new agonist ligand for ACKR4 in addition to CCL19, CCL21, and CCL25. Furthermore, CCL22, which plays an important role in both homeostasis and inflammatory responses, and is known as a ligand for CCR4 and ACKR2 was found to also act as a potent partial agonist of ACKR4. In contrast, agonist activity of CXCL13 toward ACKR4 was disproved. This independent wide-range systematic study confirms the pairing of CCL20 with ACKR4 newly discovered by Matti and co-authors, and further refines the spectrum of chemokines activating ACKR4., (©2020 Society for Leukocyte Biology.)

Interferon-β has therapeutic efficacy in Multiple Sclerosis by reducing disease exacerbations and delaying relapses. Previous studies have suggested that the effects of type I IFN in Experimental Autoimmune Encephalomyelitis (EAE) in mice were targeted to myeloid cells. We used mice with a conditional deletion (cKO) of the type I IFN receptor (IFNAR) in T regulatory (Treg) cells to dissect the role of IFN signaling on Tregs. cKO mice developed severe EAE with an earlier onset than control mice. Although Treg cells from cKO mice were more activated, the activation status and effector cytokine production of CD4 + Foxp3 - T cells in the draining lymph nodes (dLN) was similar in WT and cKO mice during the priming phase. Production of chemokines (CCL8, CCL9, CCL22) by CD4 + Foxp3 - T cells and LN resident cells from cKO mice was suppressed. Suppression of chemokine production was accompanied by a substantial reduction of myeloid derived suppressor cells (MDSCs) in the dLN of cKO mice, while generation of MDSCs and recruitment to peripheral organs was comparable. This study demonstrates that signaling by type I IFNs in Tregs reduces their capacity to suppress chemokine production, with resultant alteration of the entire microenvironment of draining lymph nodes leading to enhancement of MDSC homing, and beneficial effects on disease outcome., (Published by Elsevier Ltd.)

Administration of probiotics has been linked to immune regulation and changes in gut microbiota composition, with effects on atopic dermatitis (AD). In this study, we investigated amelioration of the symptoms of AD using Lactobacillus paracasei KBL382 isolated from the feces of healthy Koreans. Mice with Dermatophagoides farinae extract (DFE)-induced AD were fed 1 × 10 9 CFU d -1 of L. paracasei KBL382 for 4 weeks. Oral administration of L. paracasei KBL382 significantly reduced AD-associated skin lesions, epidermal thickening, serum levels of immunoglobulin E, and immune cell infiltration. L. paracasei KBL382-treated mice showed decreased production of T helper (Th)1-, Th2-, and Th17-type cytokines, including thymic stromal lymphopoietin, thymus, and activation-regulated chemokine, and macrophage-derived chemokine, and increased production of the anti-inflammatory cytokine IL-10 and transforming growth factor-β in skin tissue. Intake of L. paracasei KBL382 also increased the proportion of CD4+ CD25+ Foxp3+ regulatory T cells in mesenteric lymph nodes. In addition, administration of L. paracasei KBL382 dramatically changed the composition of gut microbiota in AD mice. Administration of KBL382 significantly ameliorates AD-like symptoms by regulating the immune response and altering the composition of gut microbiota.

Sphingosine-1-phosphate (S1P) and its receptors have been implicated in functions of Langerhans cells and atopic dermatitis. In this study, we investigated the roles of S1P receptor type 2 (S1P 2 ) in a mouse model of atopic dermatitis, which was induced by topical application of 2,4-dinitrochlorobenzene (DNCB) on ventral skin on D0, followed by repeated DNCB challenge on both ears from D7 to D49. Wild-type mice with atopic dermatitis displayed severe inflammation and mast cell accumulation in ear tissues and elevated IgE levels in serum. Furthermore, the mice showed significantly increased sizes of draining lymph nodes, high levels of inflammatory cytokines (IL-4, IL-13, IL-17, and IFN-γ) in the ears and lymph nodes and high levels of chemokines CCL17 and CCL22 in ears. Administration of JTE-013, a selective antagonist of S1P 2 (3 mg/kg, i.p, from D19 to D49) before DNCB challenge significantly suppressed DNCB-induced atopic responses in ears and lymph nodes. JTE-013 administration also significantly decreased the lymph nodes sizes, the levels of inflammatory cytokines (IL-4, IL-13, IL-17, and IFN-γ) in the ears and lymph nodes, and the levels of chemokines CCL17 and CCL22 in ears. Furthermore, the inflammatory responses of atopic dermatitis were greatly ameliorated in S1pr2 gene-deficient mice. As CCL17 and CCL22 are CCR4 ligands, acting as Th2-attracting chemokines, we investigated CCL17 and CCL22 expression in bone marrow-derived dendritic cells (BMDCs) from wild-type and S1pr2 gene-deficient mice. Addition of IL-4 (10 ng/mL) markedly increased the levels of CCL17 and CCL22, but IL-4-induced CCL17 and CCL22 expression was significantly blunted in BMDCs from S1pr2 gene-deficient mice. Furthermore, pretreatment with JTE-013 (1-30 μM) dose-dependently suppressed this induction in BMDCs from wild-type mice. Our results demonstrate that blockage of S1P 2 ameliorates not only DNCB-induced atopic dermatitis symptoms but also Th2 cell-attracting capacity of dendritic cells, suggesting S1P 2 as a potential therapeutic target for atopic dermatitis.

Background: Birthweight reflects in utero exposures and later health evolution. Despite existing studies employing high-dimensional molecular measurements, the understanding of underlying mechanisms of birthweight remains limited., Methods: To investigate the systems biology of birthweight, we cross-sectionally integrated the methylome, the transcriptome, the metabolome and a set of inflammatory proteins measured in cord blood samples, collected from four birth-cohorts (n = 489). We focused on two sets of 68 metabolites and 903 CpGs previously related to birthweight and investigated the correlation structures existing between these two sets and all other omic features via bipartite Pearson correlations., Results: This dataset revealed that the set of metabolome and methylome signatures of birthweight have seven signals in common, including three metabolites [PC(34:2), plasmalogen PC(36:4)/PC(O-36:5), and a compound with m/z of 781.0545], two CpGs (on the DHCR24 and SC4MOL gene), and two proteins (periostin and CCL22). CCL22, a macrophage-derived chemokine has not been previously identified in relation to birthweight. Since the results of the omics integration indicated the central role of cholesterol metabolism, we explored the association of cholesterol levels in cord blood with birthweight in the ENVIRONAGE cohort (n = 1097), finding that higher birthweight was associated with increased high-density lipoprotein cholesterol and that high-density lipoprotein cholesterol was lower in small versus large for gestational age newborns., Conclusions: Our data suggests that an integration of different omic-layers in addition to single omics studies is a useful approach to generate new hypotheses regarding biological mechanisms. CCL22 and cholesterol metabolism in cord blood play a mechanistic role in birthweight., Competing Interests: Declaration of competing interest None., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

The HBV-initiated hepatocellular carcinoma (HCC) frequently develops from or accompanies long-term chronic hepatitis, inflammation, and cirrhosis, and has a poor prognosis. Sorafenib, an orally active multi-kinase inhibitor, currently the most common approved drug for first-line systemic treatment of advanced HCC, only improves overall survival of three months, suggesting the need for new therapeutic strategies. In this study, we identified that sorafenib selectively resisted in immune competent C57BL/6 mice but not nude mice. The chemokines CCL22 and CCL17 were upregulated by sorafenib, which elevated dramatically higher in HBV-associated HCC. Mechanically, sorafenib accelerates CCL22 expression via TNF-α-RIP1-NF-κB signaling pathway. Blocking CCL22 signaling with antagonist C-021 and sorafenib treated in combination can inhibit tumor growth and enhance the antitumor response, whereas no significant differences in tumor burden were observed in nude mice upon addition of C-021. These findings strongly suggest that CCL22 signaling pathway strongly contributes to sorafenib resistance in HBV-associated HCC, indicating a potential therapeutic strategy for immunological chemotherapy complementing first-line agents against HBV-associated HCC., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Fetal liver (FL) is the major embryonic hematopoietic organ and a site where circulating hematopoietic stem/progenitor cells (HSPCs) reside. However, HSPC migration/retention mechanisms in FL remain unclear. A chemokine screen revealed that the CCR4 ligands CCL17 and CCL22 are highly expressed in mouse embryonic day (E) 12.5 FL. Flow cytometric analysis confirmed CCR4 expression in FL HSPCs. To identify sources of CCL17 and CCL22, we fractionated FL into various cell types and found that Ccl17 and Ccl22 were predominantly expressed in HPCs/matured HCs. In vitro cell migration analysis confirmed enhanced HSPC migration in the presence of HPCs/matured HCs. Furthermore, exo-utero injection of anti-CCR4 neutralizing antibody into pregnant mice significantly reduced the number of FL HSPCs in embryos. These data demonstrate a paracrine mechanism by which HSPC migration/retention is regulated by CCL17 and CCL22 secreted from HPCs or matured HCs in FL., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Pyropia yezoensis, a red alga, is popular and harvested a lot in East Asia and is famous for its medicinal properties attributable to its bioactive compounds including amino acids (porphyra-334 and shinorine, etc.), polysaccharides, phytosterols, and pigments, but its anti-inflammatory effect and mechanism of anti-atopic dermatitis (AD) have not been elucidated. In this study, we investigate the anti-AD effect of P. yezoensis extract (PYE) on mRNA and protein levels of the pro-inflammatory chemokines, thymus, and activation-regulated chemokine (TARC/CCL17) and macrophage-derived chemokine (MDC/CCL22), in human HaCaT keratinocyte cells treated to interferon (IFN)-γ or tumor necrosis factor (TNF)-α (10 ng/mL each). The effect of the PYE on extracellular signal-regulated kinase (ERK) and other mitogen-activated protein kinases (MAPKs) was related to its suppression of TARC and MDC production by blocking NF-κB activation in HaCaT cells. Furthermore, astaxanthin and xanthophyll from P. yezoensis were identified as anti-AD candidate compounds. These results suggest that the PYE may improve AD and contained two carotenoids by regulating pro-inflammatory chemokines., Competing Interests: The authors declare no conflicts of interest.

Background: Macrophages (Mф) can be M1/M2 polarized by Th1/2 signals, respectively. M2-like Mф are thought to be important in asthma pathogenesis, and M1-like in anti-infective immunity, however their roles in virus-induced asthma exacerbations are unknown. Our objectives were (i) to assess polarised Mф phenotype responses to rhinovirus (RV) infection in vitro and (ii) to assess Mф phenotypes in healthy subjects and people with asthma before and during experimental RV infection in vivo., Methods: We investigated characteristics of polarized/unpolarized human monocyte-derived Mф (MDM, from 3-6 independent donors) in vitro and evaluated frequencies of M1/M2-like bronchoalveolar lavage (BAL) Mф in experimental RV-induced asthma exacerbation in 7 healthy controls and 17 (at baseline) and 18 (at day 4 post infection) people with asthma., Findings: We observed in vitro: M1-like but not M2-like or unpolarized MDM are potent producers of type I and III interferons in response to RV infection (P<0.0001), and M1-like are more resistant to RV infection (P<0.05); compared to M1-like, M2-like MDM constitutively produced higher levels of CCL22/MDC (P = 0.007) and CCL17/TARC (P<0.0001); RV-infected M1-like MDM were characterized as CD14 + CD80 + CD197 + (P = 0.002 vs M2-like, P<0.0001 vs unpolarized MDM). In vivo we found reduced percentages of M1-like CD14 + CD80 + CD197 + BAL Mф in asthma during experimental RV16 infection compared to baseline (P = 0.024)., Interpretation: Human M1-like BAL Mф are likely important contributors to anti-viral immunity and their numbers are reduced in patients with allergic asthma during RV-induced asthma exacerbations. This mechanism may be one explanation why RV-triggered clinical and pathologic outcomes are more severe in allergic patients than in healthy subjects., Funding: ERC FP7 Advanced grant 233015, MRC Centre Grant G1000758, Asthma UK grant 08-048, NIHR Biomedical Research Centre funding scheme, NIHR BRC Centre grant P26095, the Predicta FP7 Collaborative Project grant 260895, RSF grant 19-15-00272, Megagrant No 14.W03.31.0024., Competing Interests: Declaration of Competing Interest Dr. Johnston reports personal fees from Therapeutic Frontiers, personal fees from Virtus Respiratory Research, personal fees from Myelo Therapeutics GmbH, personal fees from Concert Pharmaceuticals, personal fees from Bayer, personal fees from Synairgen, personal fees from Novartis, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from Gerson Lehrman Group, personal fees from resTORbio, personal fees from Bioforce, personal fees from Materia Medical Holdings, personal fees from PrepBio Pharma, personal fees from Pulmotect, personal fees from Virion Health, personal fees from Lallemand Pharma, personal fees from AstraZeneca, outside the submitted work; In addition, Dr. Johnston has a patent Wark PA, Johnston SL, Holgate ST, Davies DE. Anti-virus therapy for respiratory diseases. UK patent application No. GB 0405634.7, 12 March 2004. with royalties paid, a patent Wark PA, Johnston SL, Holgate ST, Davies DE. Interferon-Beta for Anti-Virus Therapy for Respiratory Diseases. International Patent Application No. PCT/B05/50031, 12 March 2004. with royalties paid, and a patent Davies DE, Wark PA, Holgate ST, Johnston SL. Interferon Lambda therapy for the treatment of respiratory disease. UK patent application No. 6779645.9, granted 15th August 2012. licensed. Rudolf Valenta has received research grants from the Austrian Science Fund (FWF) and Viravaxx, Vienna, Austria and serves as a consultant for Viravaxx. The other authors do not have any conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Chemotaxis is an important aspect of immune cell behavior within the tumor microenvironment (TME). One prominent example of chemotaxis within the TME is the migration of regulatory T cells (Tregs) in response to the chemokine ligands CCL17 and CCL22. Tregs within the TME cause the suppression of anti-tumor immunity and inhibition of the effect of immunotherapeutic treatments. Therefore, the ability to screen for therapeutic antibodies that can inhibit or stimulate the chemotaxis of various immune cell types is crucial. Traditionally, chemotaxis is studied by determining the number of cells in the bottom reservoir of a Transwell microplate using flow cytometry; however, this method is time-consuming and thus not appropriate for high-throughput screening purposes. The Celigo Image Cytometer has been employed to perform high-throughput cell-based assays and was used to develop a new detection method for chemotaxis measurement. The image-based detection method was developed using chemokine ligands CCL17 and CCL22 to induce the migration of CCR4 + T cells and directly count them on the bottom of the Transwell plates. Finally, the method was applied to measure the inhibitory effects of commercially available anti-CCL17 and anti-CCL22 antibodies, which caused a dose-dependent decrease in the number of migrated T cells. The proposed image cytometry method allowed screening of multiple antibodies at various concentrations, simultaneously, which can improve the efficiency for discovering potential antibody candidates that can induce or inhibit recruitment of immune cells to the tumor microenvironment., Competing Interests: Declaration of Competing Interest The author LLC declares competing financial interests. The research in this manuscript is for reporting on biological application using an instrument of Nexcelom Bioscience, LLC. The work was to demonstrate a high-throughput method for detecting T cell migration inhibition using the Celigo Image Cytometer., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Several lines of research support immune system dysregulation in psychotic disorders. However, it remains unclear whether the immunological marker alterations are stable and how they associate with brain glial cell function. This longitudinal study aimed at investigating whether peripheral immune functions are altered in the early phases of psychotic disorders, whether the changes are associated with core symptoms, remission, brain glial cell function, and whether they persist in a one-year follow-up. Two independent cohorts comprising in total of 129 first-episode psychosis (FEP) patients and 130 controls were assessed at baseline and at the one-year follow-up. Serum cyto-/chemokines were measured using a 38-plex Luminex assay. The FEP patients showed a marked increase in chemokine CCL22 levels both at baseline (p < 0.0001; Cohen's d = 0.70) and at the 12-month follow-up (p = 0.0007) compared to controls. The group difference remained significant (p = 0.0019) after accounting for relevant covariates including BMI, smoking, and antipsychotic medication. Elevated serum CCL22 levels were significantly associated with hallucinations (ρ = 0.20) and disorganization (ρ = 0.23), and with worse verbal performance (ρ = -0.23). Brain glial cell activity was indexed with positron emission tomography and the translocator protein radiotracer [ 11 C]PBR28 in subgroups of 15 healthy controls and 14 FEP patients with serum CCL22/CCL17 measurements. The distribution volume (V T ) of [ 11 C]PBR28 was lower in patients compared to controls (p = 0.026; Cohen's d = 0.94) without regionally specific effects, and was inversely associated with serum CCL22 and CCL17 levels (p = 0.036). Our results do not support the over-active microglia hypothesis of psychosis, but indicate altered CCR4 immune signaling in early psychosis with behavioral correlates possibly mediated through cross-talk between chemokine networks and dysfunctional or a decreased number of glial cells.

T cell-mediated elimination of malignant cells is one cornerstone of endogenous and therapeutically induced antitumor immunity. Tumors exploit numerous regulatory mechanisms to suppress T cell immunity. Regulatory T cells (T regs) play a crucial role in this process due to their ability to inhibit antitumoral immune responses and they are known to accumulate in various cancer entities. The chemokine CCL22, predominately produced by dendritic cells (DCs), regulates T reg migration via binding to its receptor CCR4. CCL22 controls T cell immunity, both by recruiting T regs to the tumor tissue and by promoting the formation of DC-T reg contacts in the lymph node. Here, we review the current knowledge on the role of CCL22 in cancer immunity. After revising the principal mechanisms of CCL22-induced immune suppression, we address the factors leading to CCL22 expression and ways of targeting this chemokine therapeutically. Therapeutic interventions to the CCL22-CCR4 axis may represent a promising strategy in cancer immunotherapy.

Background: CCL22 played critical roles in Tregs recruitment. The upstream regulators modulating CCL22 in hepatocellular carcinoma (HCC) were not clearly understood., Methods: MiR-23a, p-p65, p65, CCL22, and Foxp3 levels were monitored by RT-qPCR and western blotting. Immunofluorescence assay was used to perform the costaining of Foxp3 and CD4 on liver tissues. Transwell assay was applied to evaluate the migration ability of Tregs. Dual-luciferase assay was performed to determine relationship of miR-23a/CCL22 and p65/miR-23a. Chromatin immunoprecipitation (ChIP) was applied to detect the direct binding of p65 to miR-23a promoter. Xenograft tumor models were developed to investigate the functions of p65 and miR-23a in vivo., Results: HBV infection was associated with reduced survival and increased Tregs recruitment in HCC patients. MiR-23a was decreased, whereas p65, CCL22, and Foxp3 were increased in HBV + tumors. MiR-23a was inversely correlated with CCL22 and Foxp3 expression in HCC. MiR-23a directly targeted CCL22 3'UTR, leading to CCL22 reduction and attenuated Tregs recruitment. Meanwhile, p65 functioned as a transcription repressor of miR-23a by directly binding to its promoter. Inhibition of p65 induced miR-23 expression, leading to less CCL22 expression and Tregs recruitment in vitro. CCL22 was the indispensable effector underlying p65/miR-23a axis and Tregs recruitment. MiR-23a inhibitor promoted xenografted tumor growth accompanying with upregulation of CCL22, whereas p65 inhibition exerted opposite effects., Conclusion: Blockage of p65 disinhibited miR-23a expression, leading to CCL22 reduction and repress Tregs recruitment. Targeting p65/miR-23a/CCL22 axis was a novel approach for HBV + HCC treatment., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Macrophages are important for effective iron recycling and erythropoiesis, but they also play a crucial role in wound healing, orchestrating tissue repair. Recently, we demonstrated a significant accumulation of iron in healing wounds and a requirement of iron for effective repair. Herein, we sought to determine the influence of iron on macrophage function in the context of wound healing. Interestingly, wound macrophages extensively sequestered iron throughout healing, associated with a prohealing M2 phenotype. In delayed healing diabetic mouse wounds, both macrophage polarization and iron sequestration were impaired. In vitro studies revealed that iron promotes differentiation, while skewing macrophages toward a hypersecretory M2-like polarization state. These macrophages produced high levels of chemokine (C-C motif) ligands 17 and 22, promoting wound reepithelialization and extracellular matrix deposition in a human ex vivo wound healing model. Together, these findings reveal a novel, unappreciated role for iron in modulating macrophage behavior to promote subsequent wound repair. These findings support therapeutic evaluation of iron use to promote wound healing in the clinic., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Development, course of disease and prognosis of hepatocellular carcinomas (HCC) are strongly influenced by the immune system. Immunosuppressive regulatory T cells (Treg) have been shown to negatively impact disease progression and survival. To further understand the mechanisms of Treg attraction to HCC lesions, this study provides an analysis of Treg attracting chemokines in human HCC tissues. We analysed the expression of the Treg attracting chemokines CCL1 and CCL22 as well as the infiltration of FoxP3+ Treg and CD8+ T cells in paraffin-embedded tissue sections of 62 HCC patients. Expression of both chemokines was detected in 47 of 62 tissue slides. Chemokine expression was generally higher in tumour stroma and peritumoural liver tissue than in the tumour tissue itself. CD8+ T cells and FoxP3+ Treg were found at high levels in many tumour tissues. Intratumoural infiltration of Treg positively correlated with CCL22 levels in peritumoural liver tissue. In contrast, no correlation of Treg numbers and expression of CCL1 was detected. In summary, we describe here that the chemokines CCL1 and CCL22 are expressed in HCC tissues and, to a higher extent, in the stroma and peritumoural liver tissue. CCL22 may contribute to Treg recruitment and immunosuppression, whereas the role of CCL1 remains to be defined. It will be interesting to investigate the potential of these chemokines as drug targets for cancer therapy., (Copyright © 2019 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Herein, we present an efficient method that can be executed with basic laboratory skills and materials to assess lymphocyte chemokinetic movement in an ex vivo transmigration system. Group 2 innate lymphoid cells (ILC2) and CD4 + T helper cells were isolated from spleens and lungs of chicken egg ovalbumin (OVA)-challenged BALB/c mice. We confirmed the expression of CCR4 on both CD4 + T cells and ILC2, comparatively. CCL17 and CCL22 are the known ligands for CCR4; therefore, using this ex vivo transmigration method we examined CCL17 - and CCL22-induced movement of CCR4 + lymphocytes. To establish chemokine gradients, CCL17 and CCL22 were placed in the bottom chamber of the transmigration system. Isolated lymphocytes were then added to top chambers and over a 48 h period the lymphocytes actively migrated through 3 µm pores towards the chemokine in the bottom chamber. This is an effective system for determining the chemokinetics of lymphocytes, but, understandably, does not mimic the complexities found in the in vivo organ microenvironments. This is one limitation of the method that can be overcome by the addition of in situ imaging of the organ and lymphocytes under study. In contrast, the advantage of this method is that is can be performed by an entry-level technician at a much more cost-effective rate than live imaging. As therapeutic compounds become available to enhance migration, as in the case of tumor infiltrating cytotoxic immune cells, or to inhibit migration, perhaps in the case of autoimmune diseases where immunopathology is of concern, this method can be used as a screening tool. In general, the method is effective if the chemokine of interest is consistently generating chemokinetics at a statistically higher level than the media control. In such cases, the degree of inhibition/enhancement by a given compound can be determined as well.

Oral cancer, a subtype of head and neck cancer, is characterized by increased infiltrating regulatory T cells (Treg); however, the pathological significance of the increase in Tregs in disease prognosis and progression and their underlying mechanism remain unestablished. C-C motif chemokine ligand 22 (CCL22) has been implicated in the recruitment of Tregs. We used RT-qPCR to determine CCL22 mRNA expression in clinical specimens and cultured cells. Loss-of-function and gain-of-function studies were carried out to analyze the effects of CCL22 modulations on cell proliferation, migration, invasion, and tumorigenesis and the mechanism involved in the deregulation of CCL22. In oral cancer specimens, CCL22 mRNA was upregulated. The increase was not only associated with reduced disease-free survival but also strongly correlated with an increase in FOXP3 mRNA, a master regulator of Treg development and functions. Silencing CCL22 expression reduced cell proliferation, migration, and invasion, whereas ectopic overexpression showed opposite effects. Manipulation of CCL22 expression in cancer cells altered tumorigenesis in both immune-compromised and -competent mice, supporting both autonomous and non-autonomous actions of CCL22. Release of interleukin 1β (IL-1β) from cancer-associated fibroblasts (CAF) induces CCL22 mRNA expression in oral cancer cells by activating transcription factor nuclear factor kappa B (NF-κB). Our data support a model in which CAF-derived IL-1β, CCL22, and its receptor CCR4 foster a protumor environment by promoting cell transformation and Treg infiltration. Intervention of the IL-1β-CCL22-CCR4 signaling axis may offer a novel therapeutic strategy for oral cancer treatment., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: CCL22, mainly synthesized by monocyte-derived alternative (M2) macrophages, belongs to the CC family of chemokines. CCR4, the receptor for CCL22, is expressed in regulatory T cells (Tregs) and Th2 cells. The Yamamoto-Kohama (YK) mode of invasion has been associated with tumor prognosis. Herein, we investigated the role of CCL22 in the tumor microenvironment and its effect on the overall survival rate in patients with tongue squamous cell carcinoma (SCC)., Methods: Tumor sections obtained from 92 patients with tongue SCC were graded based on the mode of invasion according to the YK classification. The expressions of several markers (CCL22, CD8, and Ki-67 by immunohistochemistry; CCR4 and FoxP3 by immunofluorescent staining) were evaluated. Student's t test and chi-square tests were used to compare differences between numerical variables and groups, respectively. Survival curves were plotted according to the Kaplan-Meier method and compared using a log-rank test. Hazard ratios and 95% confidence intervals were estimated using univariate or multivariate Cox proportional hazard models., Results: The expression of CCL22 was significantly correlated with YK classification, overall survival rate (P < 0.001), a decrease in the number of CD8-positive cells, and an increase in the tumor Ki-67 index. In addition, CCR4-positive cells were observed around CCL22-positive macrophages., Conclusion: These findings indicate that the expression of CCL22 in the tumor microenvironment led to a deterioration in the prognosis of patients with tongue SCC by influencing the balance of M1- and M2-like macrophages., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Inflammatory bowel disease (IBD) is a chronic disease of the intestinal tract in which excessive activation of inflammatory response is correlated. Cyanidin-3-O-glucoside (C3G) is a powerful anti-inflammatory agent, widely existing in fruits and vegetables. However, the role of C3G has rarely been investigated in dextran sulfate sodium (DSS)-induced colitis., Methods: In an attempt to elucidate the possible mechanism of IBD and develop new efficient therapeutic methods for colitis, we evaluated the effects of C3G on DSS-induced colitis. DSS-induced colitic C57BL/6 mice were intraperitoneal injected with 1ug C3G or phosphate buffer every 2 days, a total of 3 times; the changes in macrophages and regular T cells were analyzed by flow cytometry and immunofluorescence. Cytokines and chemokines were measured by real-time quantitative polymerase chain reaction., Results: The results showed that C3G treatment did not cause changes in body weight and colon length as much as those of DSS-treated mice only. Cytokine expression levels such as interleukin (IL)- 6, IL-1β, IL-18, tumor necrosis factor α, interferon γ (IFN γ) in colons and mesenteric lymph nodes (mLNs) from C3G-treated mice were lower than those from colitic mice. Meanwhile, C3G injection inhibited the decrease in CCL22 levels and Tregs induction in colitic mice. Furthermore, the activation of macrophages by LPS and increase of CD169+ cells induced by type I IFN could be inhibited by C3G directly in vitro., Conclusions: The study is the first to demonstrate strong effects of C3G to alleviate DSS-induced colonic damage in mice. The effect of C3G on DSS-induced colitis clearly showed a decrease of CD169+ macrophages in both the colon and mLNs. An increase of CD169+ cells induced by type I IFN could be inhibited by C3G. All these data suggest that the role of C3G in colitic inflammation was mediated at least partially by CD169+ cells and the type I IFN pathway., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Evidence for a link between the pathophysiology of schizophrenia and the immune system is mounting. Altered levels of chemokines in plasma have previously been reported in patients with schizophrenia under antipsychotic medication. Here we aimed to study both peripheral and central chemokine levels in drug-naïve or short-time medicated first episode psychosis (FEP) patients., Method: We analyzed nine chemokines in plasma and CSF from 41 FEP patients and 22 healthy controls using electrochemiluminescence assay., Results: In plasma four chemokines; TARC/CCL17, eotaxin/CCL11, MDC/CCL22, IP-10/CXCL10 and in CSF one chemokine; IP-10/CXCL10 showed reliable detection in >50% of the cases. FEP patients displayed increased levels of TARC/CCL17 in plasma compared to healthy controls, 89.6 (IQR 66.2-125.8) pg/mL compared to 48.6 (IQR 28.0-71.7) pg/mL (p = 0.001). The difference was not attributed to confounding factors. Plasma TARC/CCL17 was not associated with PANSS, CGI or GAF scores, neither with cognitive functions. The chemokines eotaxin/CCL11, MDC/CCL22, IP-10/CXCL10 in plasma and IP-10/CXCL10 in CSF did not differ between FEP patients and controls., Conclusion: In line with a previous study showing that chronic patients with schizophrenia display increased plasma TARC/CCL17 levels, we here found an elevation in FEP patients suggesting a role of TARC/CCL17 in early stages of schizophrenia. The exact mechanism of this involvement is still unknown and future longitudinal studies as well as studies of central and peripheral chemokine levels would be of great interest., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Immune dysfunction often occurs in malignant pleural effusion (MPE). In our previous study, TGF-β derived predominantly from macrophages plays an important role in impairing T cell cytotoxicity in MPE. Therefore, we aimed to investigate whether other immunoregulatory cells and factors mediated TGF-β secretion from macrophages, involved in the immunosuppressive microenvironment of MPE, and to provide clues for potential immune therapy for MPE as well. We found that CCL22 level in MPE was significantly higher than that in non-malignant pleural effusion. The high level of CCL22 was closely associated with poor survival in MPE patients with lung cancer. CCL22 was dominantly produced by tumor-associated macrophages (TAMs) in MPE. Meanwhile, TAM-derived TGF-β mediated CCL22 expression in TAMs via c-Fos. CCL22 promoted the recruitment of regulatory T cells (Tregs) in MPE. Lastly, Treg-secreted high level of IL-8 further induced TGF-β production from TAMs, and promoted the immunosuppressive tumor microenvironment in MPE. Our results indicate that macrophage-derived CCL22 plays an important role in the immunosuppressive tumor microenvironment via IL-8 in MPE., (Copyright © 2019. Published by Elsevier B.V.)