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Chemokines bind to specific chemokine receptors, known as cell surface G protein-coupled receptors, constructing chemokine axes which lead to cell migration and invasion in developmental stage, pathophysiological process, and immune reactions. The chemokine axes in the tumor microenvironment are involved in tumor growth, angiogenesis, cancer stem-like cell properties, metastasis, and chemoresistance, modifying tumor immune contexture and cancer progression. Clinical features, including tumor state, grade, lymph node metastasis, and cancer subtypes, are related to the specific chemokine axes, which play a significant role in immune contexture and cell to cell interaction in the tumor microenvironment, followed by altered cancer prognosis and overall survival. The present review summarizes the role of chemokine axes in breast cancer, based on data obtained from cell line and animal models and human tumor samples. This review provides information that understand the important roles of each chemokine axis in breast cancer, probably offering a clue of adjuvant therapeutic options to improve the quality of life and survival for patients with breast cancer., (© 2024 The Author(s). Published by IMR Press.)

We currently have a large sum of clinical and experimental data documenting the involvement of numerous adipokines in the maintenance of energy homeostasis in healthy individuals and their dysregulation in diseases such as obesity, metabolic syndrome or type 2 diabetes. Despite the impressive discoveries made in this field over many years, much remains to be done before understanding all the physiological and pathological implications, and hoping for the development of other effective and safe therapeutic strategies. Two original adipokines will be taken as examples to illustrate these remarks, chemerin and neuregulin 4., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Chemokine-like receptor 1 (CMKLR1), also known as chemerin receptor 23 (ChemR23) or chemerin receptor 1, is a chemoattractant G protein-coupled receptor (GPCR) that responds to the adipokine chemerin and is highly expressed in innate immune cells, including macrophages and neutrophils. The signaling pathways of CMKLR1 can lead to both pro- and anti-inflammatory effects depending on the ligands and physiological contexts. To understand the molecular mechanisms of CMKLR1 signaling, we determined a high-resolution cryo-electron microscopy (cryo-EM) structure of the CMKLR1-Gi signaling complex with chemerin9, a nanopeptide agonist derived from chemerin, which induced complex phenotypic changes of macrophages in our assays. The cryo-EM structure, together with molecular dynamics simulations and mutagenesis studies, revealed the molecular basis of CMKLR1 signaling by elucidating the interactions at the ligand-binding pocket and the agonist-induced conformational changes. Our results are expected to facilitate the development of small molecule CMKLR1 agonists that mimic the action of chemerin9 to promote the resolution of inflammation., Competing Interests: The authors declare no competing financial interests., (Copyright: © 2023 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Fibrosis is a universal aging-related pathological process in the different organ, but is actually a self-repair excessive response. To date, it still remains a large unmet therapeutic need to restore injured tissue architecture without detrimental side effects, due to the limited clinical success in the treatment of fibrotic disease. Although specific organ fibrosis and the associated triggers have distinct pathophysiological and clinical manifestations, they often share involved cascades and common traits, including inflammatory stimuli, endothelial cell injury, and macrophage recruitment. These pathological processes can be widely controlled by a kind of cytokines, namely chemokines. Chemokines act as a potent chemoattractant to regulate cell trafficking, angiogenesis, and extracellular matrix (ECM). Based on the position and number of N-terminal cysteine residues, chemokines are divided into four groups: the CXC group, the CX3C group, the (X)C group, and the CC group. The CC chemokine classes (28 members) is the most numerous and diverse subfamily of the four chemokine groups. In this Review, we summarized the latest advances in the understanding of the importance of CC chemokine in the pathogenesis of fibrosis and aging and discussed potential clinical therapeutic strategies and perspectives aimed at resolving excessive scarring formation., Competing Interests: Conflicts of interest The authors declare that they do not have any conflicts of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Little is known about the relationships between symptomatic early severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and upper airway mucosal gene expression and immune response. To examine the association of symptomatic SARS-CoV-2 early viral load with upper airway mucosal gene expression, we profiled the host mucosal transcriptome from nasopharyngeal swab samples from 68 adults with symptomatic, mild-to-moderate coronavirus disease 19 (COVID-19). We measured SARS-CoV-2 viral load using reverse transcription-quantitative PCR (RT-qPCR). We then examined the association of SARS-CoV-2 viral load with upper airway mucosal immune response. We detected SARS-CoV-2 in all samples and recovered >80% of the genome from 95% of the samples from symptomatic COVID-19 adults. The respiratory virome was dominated by SARS-CoV-2, with limited codetection of other respiratory viruses, with the human Rhinovirus C being identified in 4 (6%) samples. This limited codetection of other respiratory viral pathogens may be due to the implementation of public health measures, like social distancing and masking practices. We observed a significant positive correlation between SARS-CoV-2 viral load and interferon signaling (OAS2, OAS3, IFIT1, UPS18, ISG15, ISG20, IFITM1, and OASL), chemokine signaling (CXCL10 and CXCL11), and adaptive immune system (IFITM1, CD300E, and SIGLEC1) genes in symptomatic, mild-to-moderate COVID-19 adults, when adjusting for age, sex, and race. Interestingly, the expression levels of most of these genes plateaued at a cycle threshold ( C T ) value of ~25. Overall, our data show that the early nasal mucosal immune response to SARS-CoV-2 infection is viral load dependent, potentially modifying COVID-19 outcomes. IMPORTANCE Several prior studies have shown that SARS-CoV-2 viral load can predict the likelihood of disease spread and severity. A higher detectable SARS-CoV-2 plasma viral load was associated with worse respiratory disease severity. However, the relationship between SARS-CoV-2 viral load, airway mucosal gene expression, and immune response remains elusive. We profiled the nasal mucosal transcriptome from nasal samples collected from adults infected with SARS-CoV-2 during spring 2020 with mild-to-moderate symptoms using a comprehensive metatranscriptomics method. We observed a positive correlation between SARS-CoV-2 viral load, interferon signaling, chemokine signaling, and adaptive immune system in adults with COVID-19. Our data suggest that early nasal mucosal immune response to SARS-CoV-2 infection was viral load dependent and may modify COVID-19 outcomes.

In this issue of Biomedical Journal we encounter the chemokine superfamily and its clinical potential. The time course from 56 days zero COVID-19 to a resurgence in cases is presented, as well as a possible solution to overcome rejection in vascularized composite allotransplantation. We are shown the opportunity deep learning (DL) offers in the case of tracking single cells and particles, and also use of DL to bring all hands on deck to counter the current challenge of the COVID-19 pandemic. This issue contains articles about the effect of low energy shock waves in cystitis; the negative effect of high fructose on aortic valve stenosis; a study about the outcome of fecal microbiota transplantation in case of refractory Clostridioides difficile infection; a novel long non-coding RNA that could serve in treating triple-negative breast cancer; the benefits of acupressure in patients with restless leg syndrome; and Filamin A mutations in abnormal neuronal migration development. Finally, a link between jaw surgery and the psychological impact on the patient is explored; a method presented that allows identification of cervical characteristics associated with difficult embryo transfer; and a letter suggesting new parameters to evaluate the use of bone-substitute augmentation in the treatment of osteoporotic intertrochanteric fractures., Competing Interests: Conflicts of interest The author declares no conflicts of interests., (Copyright © 2022 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Chemerin is an adipokine produced by the white adipose tissue and other tissues, which plays various roles in the pathogenesis of inflammatory and metabolic diseases in multiple organs. The present review aims at gathering scientific evidence reported in the last ten years, concerning the relationship of chemerin with alterations of glycaemic control, such as insulin resistance, type 2 diabetes and gestational diabetes in humans. Although the vast majority of the studies have shown a positive correlation between the chemerin level and a bad glycaemic control, a general consensus has not been reached. The reported results come from case-control and observational longitudinal studies, thereby limiting their interpretation. In fact, it cannot be stated whether insulin resistance and diabetes lead to an increase in chemerin levels or, on the contrary, if high levels of chemerin contribute to an impaired glycaemic control. Elevated levels of circulating chemerin are also associated with gestational diabetes mellitus. Chemerin gene polymorphisms could be proposed as mediators of glucose-related diseases. Nevertheless, to date very little is known about their implication in glucose metabolism. With regard to the mechanisms of action, chemerin impairs insulin cascade signaling by acting on several proteins of this cascade and by inducing inflammation., (Copyright © 2021. Published by Elsevier B.V.)

Background: Several immune mediators (IM) including cytokines, chemokines, and their receptors have been suggested to play a role in COVID-19 pathophysiology and severity., Aim: To determine if early IM profiles are predictive of clinical outcome and which of the IMs tested possess the most clinical utility., Methods: A custom bead-based multiplex assay was used to measure IM concentrations in a cohort of SARS-CoV-2 PCR positive patients (n = 326) with varying disease severities as determined by hospitalization status, length of hospital stay, and survival. Patient groups were compared, and clinical utility was assessed. Correlation plots were constructed to determine if significant relationships exist between the IMs in the setting of COVID-19., Results: In PCR positive SARS-CoV-2 patients, IL-6 was the best predictor of the need for hospitalization and length of stay. Additionally, MCP-1 and sIL-2Rα were moderate predictors of the need for hospitalization. Hospitalized PCR positive SARS-CoV-2 patients displayed a notable correlation between sIL-2Rα and IL-18 (Spearman's ρ = 0.48, P=<0.0001)., Conclusions: IM profiles between non-hospitalized and hospitalized patients were distinct. IL-6 was the best predictor of COVID-19 severity among all the IMs tested., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Although overwhelming plasma membrane integrity loss leads to cell lysis and necrosis, cells can tolerate a limited level of plasma membrane damage, undergo ESCRT-III-mediated repair, and survive. Here, we find that cells which undergo limited plasma membrane damage from the pore-forming actions of MLKL, GSDMD, perforin, or detergents experience local activation of PKCs through Ca 2+ influx at the damage sites. S660-phosphorylated PKCs subsequently activate the TAK1/IKKs axis and RelA/Cux1 complex to trigger chemokine expressions. We observe that in late-stage cancers, cells with active MLKL show expression of CXCL8. Similar expression induction is also found in ischemia-injured kidneys. Chemokines generated in this manner are also indispensable for recruiting immune cells to the dead and dying cells. This plasma membrane integrity-sensing pathway is similar to the well-established yeast cell wall integrity signaling pathway at molecular level, and this suggests an evolutionary conserved mechanism to respond to the cellular barrier damage., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Basophils, which are considered as redundant relatives of mast cells and the rarest granulocytes in peripheral circulation, have been neglected by researchers in the past decades. Previous studies have revealed their vital roles in allergic diseases and parasitic infections. Intriguingly, recent studies even reported that basophils might be associated with cancer development, as activated basophils synthesize and release a variety of cytokines and chemokines in response to cancers. However, it is still subject to debate whether basophils function as tumor-protecting or tumor-promoting components; the answer may depend on the tumor biology and the microenvironment. Herein, we reviewed the role of basophils in cancers, and highlighted some potential and promising therapeutic strategies.

Eosinophils are leukocytes which reside in the gastrointestinal tract under homeostatic conditions, except for the esophagus which is normally devoid of eosinophils. Research on eosinophils has primarily focused on anti-helminth responses and type 2 immune disorders. In contrast, the search for a role of eosinophils in chronic intestinal inflammation and fibrosis has been limited. With a shift in research focus from adaptive to innate immunity and the fact that the eosinophilic granules are filled with inflammatory mediators, eosinophils are becoming a point of interest in inflammatory bowel diseases. In the current review we summarize eosinophil characteristics and recruitment as well as the current knowledge on presence, inflammatory and pro-fibrotic functions of eosinophils in inflammatory bowel disease and other chronic inflammatory conditions, and we identify research gaps which should be covered in the future., Competing Interests: CB reports consultancy fees from Ablynx. SV reports financial support for research from MSD, AbbVie, Takeda, Pfizer, J&J, lecture fees from MSD AbbVie, Takeda, Ferring, Centocor, Hospira, Pfizer, J&J, Genentech/Roche, consultancy fees from MSD, AbbVie, Takeda, Ferring, Centocor, Hospira, Pfizer, J&J, Genentech/Roche, Celgene, Mundipharma, Celltrion, Second Genome, Prometheus, Shire, Prodigest, Gilead and Galapagos. BV reports financial support for research from Pfizer lecture fees from Abbvie, Biogen, Chiesi, Falk, Ferring, Galapagos, Janssen, MondayNightIBD, MSD, Pfizer, R-Biopharm, Takeda and Truvion, consultancy fees from Applied Strategic, Atheneum, Bristol Myers Squibb, Guidepont, Ipsos, Janssen, Progenity, Sandoz and Takeda. TV reports financial support for research from Danone and MyHealth, has served on the Speaker bureau for Abbott, Fresenius Kabi, Kyowa Kirin, Menarini, Remedus, Takeda and Will Pharma, consultancy fees from Baxter, Dr. Falk Pharma, Takeda, Tramedico, Truvion, VectivBio and Zealand Pharma. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Jacobs, Ceulemans, Wauters, Breynaert, Vermeire, Verstockt and Vanuytsel.)

Purpose: The correlation between chemerin and diabetic retinopathy (DR) has been demonstrated previously. We aimed to investigate the potential inflammatory and angiogenic roles of chemerin in DR using rat primary retinal microvascular endothelial cells (RRMECs)., Methods: RRMECs were incubated in low- and high-glucose media, and stable chemerin receptor (ChemR23) knockdown in RRMECs was established by lentiviral infection. Real-time quantitative PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and western blotting were employed to investigate the mRNA and protein expression of intercellular adhesion molecule-1 (ICAM-1), vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), and the interleukin-6 receptor (IL-6R) to explore the inflammatory and angiogenic effects of chemerin. A scratch assay was employed to evaluate the effect of chemerin on RRMEC migration., Results: Chemerin and TNF-α markedly increased the mRNA and protein expression of ICAM-1 in RRMECs (p<0.001). ChemR23 knockdown may have decreased the ICAM-1 expression under low- and high-glucose conditions (p<0.001). Even in the ChemR23-knockdown group, TNF-α significantly increased the mRNA and protein levels of ICAM-1 under low- and high-glucose conditions (p<0.001). Chemerin promoted VEGF expression under low- and high-glucose conditions. ChemR23 knockdown markedly decreased VEGF levels under low- and high-glucose conditions (p<0.05) and significantly decreased RRMEC migration (p<0.001)., Conclusions: Chemerin promotes the expression of ICAM-1, the secretion of VEGF, and the migration of RRMECs via the activation of ChemR23., (Copyright © 2021 Molecular Vision.)

Objective: B-cells are present in the inflamed arteries of giant cell arteritis (GCA) patients and a disturbed B-cell homeostasis is reported in peripheral blood of both GCA and the overlapping disease polymyalgia rheumatica (PMR). In this study, we aimed to investigate chemokine-chemokine receptor axes governing the migration of B-cells in GCA and PMR., Methods: We performed Luminex screening assay for serum levels of B-cell related chemokines in treatment-naïve GCA (n = 41), PMR (n = 31) and age- and sex matched healthy controls (HC, n = 34). Expression of chemokine receptors on circulating B-cell subsets were investigated by flow cytometry. Immunohistochemistry was performed on GCA temporal artery (n = 14) and aorta (n = 10) and on atherosclerosis aorta (n = 10) tissue., Results: The chemokines CXCL9 and CXCL13 were significantly increased in the circulation of treatment-naïve GCA and PMR patients. CXCL13 increased even further after three months of glucocorticoid treatment. At baseline CXCL13 correlated with disease activity markers. Peripheral CXCR3+ and CXCR5+ switched memory B-cells were significantly reduced in both patient groups and correlated inversely with their complementary chemokines CXCL9 and CXCL13. At the arterial lesions in GCA, CXCR3+ and CXCR5+ B-cells were observed in areas with high CXCL9 and CXCL13 expression., Conclusion: Changes in systemic and local chemokine and chemokine receptor pathways related to B-cell migration were observed in GCA and PMR mainly in the CXCL9-CXCR3 and CXCL13-CXCR5 axes. These changes can contribute to homing and organization of B-cells in the vessel wall and provide further evidence for an active involvement of B-cells in GCA and PMR., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

IL-33-associated type 2 innate immunity has been shown to support beige fat formation and thermogenesis in subcutaneous inguinal white adipose tissue (iWAT), but little is known about how it is regulated in iWAT. Chemerin, as a newly identified adipokine, is clinically associated with obesity and metabolic disorders. We here show that cold exposure specifically reduces chemerin and its receptor chemerin chemokine-like receptor 1 (CMKLR1) expression in iWAT. Lack of chemerin or adipocytic CMKLR1 enhances cold-induced thermogenic beige fat via potentiating type 2 innate immune responses. Mechanistically, we identify adipocytes, particularly beige adipocytes, as the main source for cold-induced IL-33, which is restricted by the chemerin-CMKLR1 axis via dampening cAMP-PKA signaling, thereby interrupting a feed-forward circuit between beige adipocytes and type 2 innate immunity that is required for cold-induced beige fat and thermogenesis. Moreover, specific deletion of adipocytic IL-33 inhibits cold-induced beige fat and type 2 innate immune responses. Last, genetic blockade of adipocytic CMKLR1 protects against diet-induced obesity and enhances the metabolic benefits of cold stimulation in preestablished obese mice. Thus, our study identifies the chemerin-CMKLR1 axis as a physiological negative regulator of thermogenic beige fat via interrupting adipose-immune communication and suggests targeting adipose CMKLR1 as a potential therapeutic strategy for obesity-related metabolic disorders., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Apart from its role in inflammation and immunity, chemerin is also involved in white adipocyte biology. To study the role of chemerin in adipocyte metabolism, we examined the function of chemerin in brown adipose tissue. Brown and white adipocyte precursors were differentiated into adipocytes in the presence of Chemerin siRNA. Chemerin-deficient (Chem -/- ) mice were compared to wild-type mice when fed a high-fat diet. Chemerin is expressed during brown adipocyte differentiation and knock down of chemerin mRNA results in decreased brown adipocyte differentiation with reduced fatty acid uptake in brown adipocytes. Chem -/- mice are leaner than wild-type mice but gain more weight when challenged with high-fat diet feeding, resulting in a larger increase in fat deposition. Chem -/- mice develop insulin resistance when on a high-fat diet or due to age. Brown adipose depots in Chem -/- mice weigh more than in wild-type mice, but with decreased mitochondrial content and function. Compared to wild-type mice, male Chem -/- mice have decreased oxygen consumption, CO 2 production, energy expenditure, and a lower respiratory exchange ratio. Additionally, body temperature of Chem -/- mice is lower than that of wild-type mice. These results revealed that chemerin is expressed during brown adipocyte differentiation and has a pivotal role in energy metabolism through brown adipose tissue thermogenesis., (© 2021 Federation of American Societies for Experimental Biology.)

This study aimed to examine the expression and clinical significance of chemokine-like factor-like MARVEL transmembrane domain-containing family member 8 (CMTM8) in gastric cancer (GC). The mRNA and protein expression of CMTM8 were detected by bioinformatics analysis and immunohistochemistry (IHC), respectively. Bioinformatics analysis found that there was a high mRNA expression of CMTM8 in GC tissues, but failed to identify a significant relationship with the clinicopathological features or prognosis of GC patients. However, IHC results showed that the positive expression of CMTM8 protein in GC tissues was significantly lower than that of adjacent nontumor tissues and correlated with differentiation, tumor node metastasis stage, and distal metastasis of GC patients ( p  < 0.05). Moreover, the survival time of GC patients with negative CMTM8 protein expression group was shorter than that of positive CMTM8 protein expression group by Kaplan-Meier survival analysis ( p  < 0.05). Cox proportional hazards model (COX) regression analysis indicated that CMTM8 protein was an independent protective factor for the overall survival of GC patients. Further Gene Set Enrichment Analysis suggested that CMTM8 may be involved in regulating the calcium signaling pathway, cell adhesion molecules, and cytokine-cytokine receptor interaction in GC. Our study shows that CMTM8 protein is downregulated in GC tissues, and CMTM8 protein expression is related to GC metastasis and the prognosis of GC patients.

Removal of apoptotic cells is essential for maintenance of tissue homeostasis. Chemotactic cues termed "find-me" signals attract phagocytes toward apoptotic cells, which selectively expose the anionic phospholipid phosphatidylserine (PS) and other "eat-me" signals to distinguish healthy from apoptotic cells for phagocytosis. Blebs released by apoptotic cells can deliver find-me signals; however, the mechanism is poorly understood. Here, we demonstrate that apoptotic blebs generated in vivo from mouse thymus attract phagocytes using endogenous chemokines bound to the bleb surface. We show that chemokine binding to apoptotic cells is mediated by PS and that high affinity binding of PS and other anionic phospholipids is a general property of many but not all chemokines. Chemokines are positively charged proteins that also bind to anionic glycosaminoglycans (GAGs) on cell surfaces for presentation to leukocyte G protein-coupled receptors (GPCRs). We found that apoptotic cells down-regulate GAGs as they up-regulate PS on the cell surface and that PS-bound chemokines, unlike GAG-bound chemokines, are able to directly activate chemokine receptors. Thus, we conclude that PS-bound chemokines may serve as find-me signals on apoptotic vesicles acting at cognate chemokine receptors on leukocytes., Competing Interests: The authors have declared that no competing interests exist.

SARS-COV-2 infection represents the greatest pandemic of the world, counting daily increasing number of subjects positive to the virus and, sadly, increasing number of deaths. Current studies reported that the cytokine/chemokine network is crucial in the onset and maintenance of the "cytokine storm", the event occurring in those patients in whom the progression of COVID-19 will progress, in most cases, to a very severe and potentially threatening disease. Detecting a possible "immune signature" in patients, as assessed by chemokines status in patients with COVID-19, could be helpful for individual risk stratification for developing a more or less severe clinical course of the disease. The present review is specifically aimed at overviewing current evidences provided by in vitro and in vivo studies addressing the issue of which chemokines seems to be involved, at least at present, in COVID-19. Currently available experimental and clinical studies regarding those chemokines more deeply studied in COVID-19, with a specific focus on their role in the cytokine storm and ultimately with their ability to predict the clinical course of the disease, will be taken into account. Moreover, similarities and differences between chemokines and cytokines, which both contribute to the onset of the pro-inflammatory loop characterizing SARS-COV-2 infection, will be briefly discussed. Future studies will rapidly accumulate in the next months and their results will hopefully provide more insights as to the complex physiopathology of COVID-19-related cytokine storm. This will likely make the present review somehow "dated" in a short time, but still the present review provides an overview of the scenario of the current knowledge on this topic., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The members of the B7 family, as immune checkpoint molecules, can substantially regulate immune responses. Since microRNAs (miRs) can regulate gene expression post-transcriptionally, we conducted a scoping review to summarize and discuss the regulatory cross-talk between miRs and new B7 family immune checkpoint molecules, i.e., B7-H3, B7-H4, B7-H5, butyrophilin like 2 (BTNL2), B7-H6, B7-H7, and immunoglobulin like domain containing receptor 2 (ILDR2). The current study was performed using a six-stage methodology structure and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. PubMed, Embase, Scopus, Cochrane, ProQuest, and Google Scholar were systematically searched to obtain the relevant records to 5 November 2020. Two authors independently reviewed the obtained records and extracted the desired data. After quantitative and qualitative analyses, we used bioinformatics approaches to extend our knowledge about the regulatory cross-talk between miRs and the abovementioned B7 family members. Twenty-seven articles were identified that fulfilled the inclusion criteria. Studies with different designs reported gene-miR regulatory axes in various cancer and non-cancer diseases. The regulatory cross-talk between the aforementioned B7 family molecules and miRs might provide valuable insights into the pathogenesis of various human diseases.

Neutrophils are the most prevalent leukocytes in the human body. They have a pivotal role in the innate immune response against invading bacterial and fungal pathogens, while recent emerging evidence also demonstrates their role in cancer progression and anti-tumor responses. The efficient execution of many neutrophil effector responses requires the presence of β 2 integrins, in particular CD11a/CD18 or CD11b/CD18 heterodimers. Although extensively studied at the molecular level, the exact signaling cascades downstream of β 2 integrins still remain to be fully elucidated. In this review, we focus mainly on inside-out and outside-in signaling of these two β 2 integrin members expressed on neutrophils and describe differences between various neutrophil stimuli with respect to integrin activation, integrin ligand binding, and the pertinent differences between mouse and human studies. Last, we discuss how integrin signaling studies could be used to explore the therapeutic potential of targeting β 2 integrins and the intracellular signaling cascade in neutrophils in several, among other, inflammatory conditions in which neutrophil activity should be dampened to mitigate disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bouti, Webbers, Fagerholm, Alon, Moser, Matlung and Kuijpers.)

Pro-inflammatory cytokine and chemokines genes drive prostate cancer progression and metastasis: molecular mechanism update and the science that underlies racial disparity. comprehensive review article. Isaac J. Powell, S. Chinni, S.S. Reddy, Alexander Zaslavsky, Navnath Gavande Introduction: In 2013 we reported that with the use of bioinformatics and ingenuity pathway network analysis we were able to identify functional driver genes that were differentially expressed among a large population of African American men (AAM) and European American men (EAM). Pro-inflammatory cytokine genes were found to be more interactive and more expressed among AAM and have been found to be functional drivers of aggressive prostate cancer (CaP) and aggressiveness in other solid tumors. We examined these genes and biological pathways initiated by these cytokines in primary CaP tissue. Method We unravel the gene network and identified biologic pathways that impacted activation of the androgen receptor, mesenchymal epithelial transition (invasion) and chemokines associated with metastasis in the CaP tissue from 639 radical prostatectomy specimens. Results Biologic pathways identified by unraveling pro-inflammatory genes from our network, more expressed among AAM compared to EAM, were tumor necrosis factor (TNF), IL1b, IL6, and IL8. IL6 and IL8 are downstream of TNF activity and are known activators of androgen receptor and through mediators promote CaP cell proliferation. TNF and IL1b mediate tumor cell invasiveness through the activation of MMP (matrix metalloproteinase) which down regulates E-Cadherin to initiate epithelial mesenchymal transition which allows cells to become invasive in the microenvironment. Ultimately our network analysis indicates that TNF and IL1b activate CXCR4 receptor on CaP cells, which facilitates metastatic progression reportedly by binding to CXCL12 on lipid rafts and tumor implantation in the bone marrow. Conclusion Our retrospective biologic mechanistic model reveals a set of pro-inflammatory cytokines and chemokines that drive CaP aggressiveness, tumor heterogeneity, progression and metastasis. A prospective multi-institutional study needs to be conducted for clinical validation as well consideration of targeted therapy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Microglia are immune cells resident in the central nervous system (CNS). It has been gradually clarified that microglia play various roles at the developmental stage of the CNS. From embryonic to early postnatal age, microglia remove apoptotic cells by phagocytosis and refine the neural circuits by synaptic pruning. In addition, microglia promote the proliferation and differentiation of neural stem cells by releasing physiologically active substances. Our group has focused on the physiological actions of microglia via cytokines and chemokines at the early postnatal developmental stage. We found that a large number of activated microglia accumulate in the early postnatal subventricular zone (SVZ). We demonstrated that the these SVZ microglia facilitate neurogenesis and oligodendrogenesis via inflammatory cytokines including IL-1β, TNFα, IL-6, IFNγ. We have also found that microglia regulate the functional maturation of the blood brain barrier (BBB) and identified the cytokines and chemokines involved in the effects of microglia. These findings indicate that microglia are physiologically more important than ever thought to reveal robust brain functions. Furthermore, the new mode of microglial action may lead to the discovery of drug targets of the incurable CNS diseases.

The novel coronavirus (SARS-CoV-2) is primarily a respiratory pathogen and its clinical manifestations are dominated by respiratory symptoms, the most severe of which is acute respiratory distress syndrome (ARDS). However, COVID-19 is increasingly recognized to cause an overwhelming inflammatory response and cytokine storm leading to end organ damage. End organ damage to heart is one of the most severe complications of COVID-19 that increases the risk of death. We proposed a two-fold mechanism responsible for causing acute coronary events in patients with COVID-19 infection: Cytokine storm leading to rapid onset formation of new coronary plaques along with destabilization of pre-existing plaques and direct myocardial injury secondary to acute systemic viral infection. A well-coordinated immune response is the first line innate immunity against a viral infection. However, an uncoordinated response and hypersecretion of cytokines and chemokines lead to immune related damage to the human body. Human Coronavirus (HCoV) infection causes infiltration of inflammatory cells that cause excessive production of cytokines, proteases, coagulation factors, oxygen radicals and vasoactive molecules causing endothelial damage, disruption of fibrous cap and initiation of formation of thrombus. Systemic viral infections also cause vasoconstriction leading to narrowing of vascular lumen and stimulation of platelet activation via shear stress. The resultant cytokine storm causes secretion of hypercoagulable tissue factor without consequential increase in counter-regulatory pathways such as AT-III, activated protein C and plasminogen activator type 1. Lastly, influx of CD4+ T-cells in cardiac vasculature results in an increased production of cytokines that stimulate smooth muscle cells to migrate into the intima and generate collagen and other fibrous products leading to advancement of fatty streaks to advanced atherosclerotic lesions. Direct myocardial damage and cytokine storm leading to destabilization of pre-existing plaques and accelerated formation of new plaques are the two instigating mechanisms for acute coronary syndromes in COVID-19., 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., (Published by Elsevier Ltd.)

Background: We previously reported that the adipokine chemerin, when added exogenously to the isolated rat mesenteric artery, amplified electrical field-stimulated (EFS) contraction. The Chemerin1 antagonist CCX832 alone inhibited EFS-induced contraction in tissues with but not without perivascular adipose tissue (PVAT). These data suggested indirectly that chemerin itself, presumably from the PVAT, facilitated EFS-induced contraction. We created the chemerin KO rat and now test the focused hypothesis that endogenous chemerin amplifies EFS-induced arterial contraction. Methods: The superior mesenteric artery +PVAT from global chemerin WT and KO female rats, with endothelium and sympathetic nerve intact, were mounted into isolated tissue baths for isometric and EFS-induced contraction. Results: CCX832 reduced EFS (2-20 Hz)-induced contraction in tissues from the WT but not KO rats. Consistent with this finding, the magnitude of EFS-induced contraction was lower in the tissues from the KO vs. WT rats, yet the maximum response to the adrenergic stimulus PE was not different among all tissues. Conclusion: These studies support that endogenous chemerin modifies sympathetic nerve-mediated contraction through Chemerin1, an important finding relative in understanding chemerin's role in control of blood pressure.

Chronic pain resulting from nerve injury, tissue inflammation, and tumor invasion or treatment, is a major health problem impacting the quality of life and producing a significant economic and social burden. However, the current analgesic drugs including non-steroidal anti-inflammatory drugs and opioids are inadequate to relieve chronic pain due to the lack of efficacy or severe side-effects. Chemokines are a family of small secreted proteins that bind to G protein-coupled receptors to trigger intracellular signaling pathways and direct cell migration, proliferation, survival, and inflammation under homeostatic and pathological conditions. Accumulating evidence supports the important role of chemokines and chemokine receptors in the peripheral and central nervous system in mediating chronic pain via enhancing neuroinflammation. In this review, we focus on recent progress in understanding the comprehensive roles of chemokines and chemokine receptors in the generation and maintenance of different types of chronic pain, including neuropathic pain, inflammatory pain, cancer pain, and visceral pain. The current review also summarizes the upstream signaling of transcriptional and epigenetic regulation on the expression of chemokines and chemokine receptors as well as the downstream signaling of chemokine receptors underlying chronic pain. As chronic itch and chronic pain share some common mechanisms, we also discuss the emerging roles of chemokines and chemokine receptors in chronic itch. Targeting specific chemokines or chemokine receptors by siRNAs, blocking antibodies, or small-molecule antagonists may offer new therapeutic potential for the management of chronic pain., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Atopic dermatitis (AD) is a common relapsing inflammatory skin disease characterized by severe pruritus that seriously affects the quality of patients' life. There is an increasingly large amount of research demonstrating that traditional Chinese medicine (TCM) including herbal formulae and bioactive ingredients exerts pharmacological effects on atopic dermatitis. It has been a long history of TCM being used to treat atopic dermatitis, especially in preventing disease recurrence, maintaining long-term remission, and reducing disease burden. Nowadays, both of TCM monomer preparations and traditional formulae are still widely used. This review focuses on TCM as well as its bioactive ingredients for the treatment of AD, from the perspectives of animal model construction, pharmacodynamic mechanisms and clinical studies of formulae. To be more specific, the regulation and molecular mechanisms of the herbal formulae and bioactive ingredients of TCM are investigated, and the latest clinical research on TCM formulae is discussed. Furthermore, it provides a summary of the strengths and utilities of TCM, and will be useful for doctors who use Chinese medicine for treatment or researchers who select candidates for clinical treatments or further high-quality clinical studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Neurodevelopment and mature brain function are spatiotemporally regulated by various cytokines and chemokines. The chemokine-like neuropeptide FAM19A1 is a member of family with sequence similarity 19 (FAM19), which is predominantly expressed in the brain. Its highly conserved amino acid sequence among vertebrates suggests that FAM19A1 may play important physiological roles in neurodevelopment and brain function. Here we used a LacZ reporter gene system to map the expression pattern of the FAM19A1 gene in the mouse brain. The FAM19A1 expression was observed in several brain regions starting during embryonic brain development. As the brain matured, the FAM19A1 expression was detected in the pyramidal cells of cortical layers 2/3 and 5 and in several limbic areas, including the hippocampus and the amygdala. FAM19A1-deficient mice were used to evaluate the physiological contribution of FAM19A1 to various brain functions. In behavior analysis, FAM19A1-deficient mice exhibited several abnormal behaviors, including hyperactive locomotor behavior, long-term memory deficits and fear acquisition failure. These findings provide insight into the potential contributions of FAM19A1 to neurodevelopment and mature brain function.

Osteonecrosis of the femoral head (ONFH) is a common and disabling joint disease. Although there is no clear consensus on the complex pathogenic mechanism of ONFH, trauma, abuse of glucocorticoids, and alcoholism are implicated in its etiology. The therapeutic strategies are still limited, and the clinical outcomes are not satisfactory. Mesenchymal stem cells (MSCs) have been shown to exert a positive impact on ONFH in preclinical experiments and clinical trials. The beneficial properties of MSCs are due, at least in part, to their ability to home to the injured tissue, secretion of paracrine signaling molecules, and multipotentiality. Nevertheless, the regenerative capacity of transplanted cells is impaired by the hostile environment of necrotic tissue in vivo , limiting their clinical efficacy. Recently, genetic engineering has been introduced as an attractive strategy to improve the regenerative properties of MSCs in the treatment of early-stage ONFH. This review summarizes the function of several genes used in the engineering of MSCs for the treatment of ONFH. Further, current challenges and future perspectives of genetic manipulation of MSCs are discussed. The notion of genetically engineered MSCs functioning as a "factory" that can produce a significant amount of multipotent and patient-specific therapeutic product is emphasized.

Since chemerin's identification as an adipokine, it has been associated with a number of human diseases including diabetes and obesity. However, the basic scientific foundation for these clinical determinations is still lacking. Fibroblastic mouse 3T3 cells are unable to develop lipid droplets if chemerin is not present. Thus, we hypothesized that an in vivo rat model chemerin knockout (KO; an advancement from the previously mentioned in vitro cultures) would have limited accumulation of lipid in adipocytes compared to their wild-type (WT) counterparts. Female WT/KO rats (Sprague Dawley background) were fed a low-fat diet starting at 8 weeks of age with weekly body weight and food consumption monitoring. At 25 weeks of age, adipose tissue depots were dissected and flash frozen for PCR analysis or fixed with paraformaldehyde for histology. Over the 17 weeks of experimentation, WT and KO animals did not have differences in total body weight or food consumption but KO animals had a significantly reduced amount of visceral fat compared to WT animals (via microCT at 8 and 25 weeks). Histology of retroperitoneal and mesenteric depots demonstrated a significant leftward shift in adipocyte size in the mesenteric but not the retroperitoneal depot of the KO compared to WT animals. Similarly, in the mesenteric fat of the KO rat, gene expression of adiponectin, fatty acid synthase, perilipin, and leptin were significantly reduced compared to mesenteric fat of WT animals and retroperitoneal fat of both WT and KO animals. Adiponectin was highlighted by a protein-protein interaction network as being important for the physiological effects of chemerin removal. These data are the first, to our knowledge, to demonstrate chemerin's adipokine potential in vivo and identify it as fat depot location-specific., Competing Interests: The authors have declared that no competing interests exist.

Accumulating evidence suggests that the inhibition of neuroinflammation is a potential target for therapeutic or preventive strategies for Alzheimer's disease (AD). Chemerin has attracted particular attention for its role in the regulation of inflammation. In addition, amyloid β 1-42 (Aβ 1-42 ) can interact with chemokine-like receptor 1 (CMKLR1), the receptor for chemerin, and induce microglial chemotaxis. Meanwhile, CMKLR1 is expressed in the brain, and both chemerin and Aβ 1-42 share the same receptor. Thus, we hypothesized that chemerin (C9), a chemerin-derived nonapeptide, may have the potential to ameliorate Aβ 1-42 mediated AD disease progression. The results showed that an intracerebroventricular (i.c.v.) injection of C9 (8 µg/kg) facilitated memory formation and improved memory retention, as evidenced by the results of both the novel object recognition test (NOR) and object location recognition (OLR) tasks. These memory-enhancing effects of C9 were also observed after C9 (2 µg/kg) was infused into the hippocampus. Moreover, we found that treatment with C9 reversed the deficits in memory and learning ability induced by oligomeric Aβ 1-42 . Meanwhile, C9 also significantly inhibited Aβ 1-42 -induced increases in the levels of pro-inflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the hippocampus. The same results were obtained for Western blotting and enzyme-linked immunosorbent assay (ELISA) experiments. Finally, we observed that C9 did not affect locomotor activity, suggesting that its improvement of memory is not a false positive induced by hypolocomotion. In conclusion, C9 may facilitate memory formation, prolong memory retention, and ameliorate Aβ 1-42 -induced memory impairment, suggesting that C9 may potentially represent a novel strategy for the treatment of AD.

Oligodendrocyte and neural precursor cells (OPCs and NPCs, respectively) in the central nervous system (CNS) have diverse roles in development and homeostasis. During development, precursors build the CNS. In adulthood, they maintain their ability to proliferate and generate differentiated progeny, indicating their tremendous potential to regenerate and repair injured or degenerated CNS. How can we utilize this capability? Cross-talk between neurons and OPCs may hold some clues. Neurons communicate with OPCs via two mechanisms: 1) paracrine secretion of ligands, and 2) neuronal activity and bona fide synapses with OPCs. Intriguingly, OPCs express receptors for chemokines, which are small signalling molecules produced by various cells, including neurons. In addition to inducing chemotaxis, chemokines also regulate cell proliferation, survival and differentiation. In this review, we will summarize the roles of neuronally secreted chemokines and their documented ability to directly regulate the diverse functions of OPCs and NPCs in the developing as well as adult normal and injured CNS. We will focus on the following neuronal chemokines: CCL2, CCL3, CCL20, CCL21, CXCL1, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12 and CX3CL1. We will discuss the implications for neuronal chemokine signalling in OPCs and NPCs not only in developmental myelination and adult CNS regeneration, but also in cognition, behavior, neuroinflammation and neuronal function., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Some of the current challenges and complications of cancer therapy are chemotherapy- induced peripheral neuropathy (CIPN) and the neuropathic pain that are associated with this condition. Many major chemotherapeutic agents can cause neurotoxicity, significantly modulate the immune system and are always accompanied by various adverse effects. Recent evidence suggests that cross-talk occurs between the nervous system and the immune system during treatment with chemotherapeutic agents; thus, an emerging concept is that neuroinflammation is one of the major mechanisms underlying CIPN, as demonstrated by the upregulation of chemokines. Chemokines were originally identified as regulators of peripheral immune cell trafficking, and chemokines are also expressed on neurons and glial cells in the central nervous system., Objective: In this review, we collected evidence demonstrating that chemokines are potential mediators and contributors to pain signalling in CIPN. The expression of chemokines and their receptors, such as CX3CL1/CX3CR1, CCL2/CCR2, CXCL1/CXCR2, CXCL12/CXCR4 and CCL3/CCR5, is altered in the pathological conditions of CIPN, and chemokine receptor antagonists attenuate neuropathic pain behaviour., Conclusion: By understanding the mechanisms of chemokine-mediated communication, we may reveal chemokine targets that can be used as novel therapeutic strategies for the treatment of CIPN., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cytokines and chemokines play diverse roles in different organ systems. Family with sequence similarity 19, member A1-5 (FAM19A1-A5; also known as TAFA1-5) is a group of conserved chemokine-like proteins enriched in the CNS of mice and humans. Their functions are only beginning to emerge. Here, we show that the expression of Fam19a1-a5 in different mouse brain regions are induced or suppressed by unfed and refed states. The striking nutritional regulation of Fam19a family members in the brain suggests a potential central role in regulating metabolism. Using a knockout (KO) mouse model, we show that loss of FAM19A1 results in sexually dimorphic phenotypes. In male mice, FAM19A1 deficiency alters food intake patterns during the light and dark cycle. Fam19a1 KO mice are hyperactive, and locomotor hyperactivity is more pronounced in female KO mice. Behavior tests indicate that Fam19a1 KO female mice have reduced anxiety and sensitivity to pain. Spatial learning and exploration, however, is preserved in Fam19a1 KO mice. Altered behaviors are associated with elevated norepinephrine and dopamine turnover in the striatum. Our results establish an in vivo function of FAM19A1 and highlight central roles for this family of neurokines in modulating animal physiology and behavior.-Lei, X., Liu, L., Terrillion, C. E., Karuppagounder, S. S., Cisternas, P., Lay, M., Martinelli, D. C., Aja, S., Dong, X., Pletnikov, M. V., Wong, G. W. FAM19A1, a brain-enriched and metabolically responsive neurokine, regulates food intake patterns and mouse behaviors.

Purpose: The state of knowledge about the effect of sleep deprivation on the immune system is scarce and conflicting. It would therefore be useful to investigate the consequences of sleep deprivation on the immune system. We have studied the effect of sleep deprivation on the changes in neutrophil functions, and the ex vivo proliferative pattern of CD4 + T lymphocytes in relationship with blood cytokine and chemokine levels due to the crucial role of these cells in mounting potent immune responses., Methods: Healthy volunteers were followed for 3 weeks. They had normal sleep in weeks 1 and 3 and they were sleep-deprived on week 2, sleeping < 6 h per 24 h, a pattern similar to sleep behaviors of many chronically sleep-deprived individuals. We assessed the levels of Th1/Th2 and inflammatory cytokines and chemokines, CD4 + T cells, and the NADPH oxidase activation and phagocytic functions in neutrophils., Results: Our results suggest that sleep deprivation leads to a decreased neutrophil capacity to phagocytose bacteria and activate NADPH oxidase (p < 0.05). Sleep deprivation was associated with a potential increase in CXCL9 levels and decrease in CXCL10/CXCL9 and CCL5/CXCL9 ratios (p < 0.05). Furthermore, our results suggest that the decrease in CD4 + T cell due to sleep deprivation was not associated with changes in their proliferation as observed by Ki67 levels, but rather, it correlated with changes in CXCL10/CXCL9 ratio (p < 0.05)., Conclusions: Sleep deprivation may lead to a decreased phagocytosis and NADPH oxidase activity in neutrophils and a decrease in the levels of CD4 + T cells which is related to changes in the Th1-related chemokine balance.

The role of negative checkpoint regulators (NCRs) in human health and disease cannot be overstated. V-domain Ig-containing Suppressor of T-cell Activation (VISTA) is an Ig superfamily protein predominantly expressed within the hematopoietic compartment and has been studied for its role in the negative regulation of T cell responses. The findings presented in this study show that, unlike all other NCRs, VISTA deficiency dramatically impacts on macrophage cytokine and chemokine production, as well as the chemotactic response of VISTA-deficient macrophages. A select group of inflammatory chemokines, including CCL2, CCL3, CCL4, and CCL5, was strikingly elevated in culture supernatants from VISTA KO macrophages. VISTA deficiency also altered chemokine receptor recycling and profoundly disrupted myeloid chemotaxis. The impact of VISTA deficiency on chemotaxis in vivo was apparent with the reduced ability of both KO macrophages and MDSCs to migrate to the tumor microenvironment. This is the first demonstration of an NCR impacting on myeloid mediator production and chemotaxis, and will guide the use of anti-VISTA therapeutics to manipulate the chemotaxis of inflammatory macrophages or immunosuppressive MDSCs in inflammatory diseases and cancer., (Copyright © 2019 Broughton, ElTanbouly, Schaafsma, Deng, Sarde, Croteau, Li, Nowak, Mabaera, Smits, Kuta, Noelle and Lines.)

Prostate cancer (PC) is a leading cause of death in men. Inflammation is one of the initiating processes whereby cells are trafficked into the tumor microenvironment by specific cytokines termed chemokines. This recruitment is complex and involves diverse leukocyte subsets with procancer and anticancer functions. Chemokines promote/abrogate proliferation of cancerous cells, block/aid apoptosis, and are instrumental/detrimental in cancer cell migration required for metastasis. Chemokines guide the release/transport of immune cells that serve as chaperones at sites of inflammation, and after subsequent activation, they lead to an immune response. The variety of immune cells recruited at the site of tumor initiation possess unique functions, and the plethora of chemokines released by each cell derived from a progenitor cell activated under a defined set of conditions dictates its specific role in cancer progression/regression. Geographic consequences that govern the climate and endemic diseases, along with the associated evolutionary effects that at times protect populations from one disease, could lead to genetic variations that determine a role for ethnicity and race in PC risk and susceptibility. Dysregulated expression or an imbalance in the homeostatic mechanisms associated with chemokines is implicated in PC. This review discusses the role of inflammation and chemokines in PC., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Chronic pain is a debilitating condition that often emerges as a clinical symptom of inflammatory diseases. It has therefore been widely accepted that the immune system critically contributes to the pathology of chronic pain. Microglia, a type of immune cell in the central nervous system, has attracted researchers' attention because in rodent models of neuropathic pain that develop strong mechanical and thermal hypersensitivity, histologically activated microglia are seen in the dorsal horn of spinal cord. Several kinds of cytokines are generated by damaged peripheral neurons and contribute to microglial activation at the distal site of the injury where damaged neurons send their projections. Microglia are known as key players in the surveillance of the local environment in the central nervous system and have a significant role of circuit remodeling by physical contact to synapses. Key molecules for the pathology of neuropathic pain exist in the activated microglia, but the factors driving pain-inducible microglial activation remain unclear. Therefore, to find the key molecules inducing activation of spinal microglia and to figure out the precise mechanism of how microglia modulate neuronal circuits in the spinal cord to form chronic pain state is a critical step for developing effective treatment of neuropathic pain., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Dendritic cells (DCs) are the most effective professional antigen-presenting cell. They ferry antigen from the extremities to T cells and are essential for the initiation of an adaptive immune response. Despite interest in how DCs respond to chemical stimuli, there have been few attempts to model DC migration. In this paper, we simulate the motility of DCs by modeling the generation of forces by filopodia and a force balance on the cell. The direction of fliopodial extension is coupled to differential occupancy of cognate chemokine receptors across the cell. Our model simulates chemokinesis and chemotaxis in a variety of chemical and mechanical environments. Simulated DCs undergoing chemokinesis were measured to have a speed of 5.1 ± 0.07 μm·min-1 and a persistence time of 3.2 ± 0.46 min, consistent with experiment. Cells undergoing chemotaxis exhibited a stronger chemotactic response when exposed to lower average chemokine concentrations, also consistent with experiment. We predicted that when placed in two opposing gradients, cells will cluster in a line, which we call the "line of equistimulation;" this clustering has also been observed. We calculated the effect of varying gradient steepness on the line of equistimulation, with steeper gradients resulting in tighter clustering. Moreover, gradients are found to be most potent when cells are in a gradient of chemokine whose mean concentration is close to the binding of the Kd to the receptor, and least potent when the mean concentration is 0.1Kd. Comparing our simulations to experiment, we can give a quantitative measure of the strength of certain chemokines relative to others. Assigning the signal of CCL19 binding CCR7 a baseline strength of 1, we found CCL21 binding CCR7 had a strength of 0.28, and CXCL12 binding CXCR4 had a strength of 0.30. These differences emerge despite both chemokines having virtually the same Kd, suggesting a mechanism of signal amplification in DCs requiring further study., Competing Interests: The authors have declared that no competing interests exist.

CKLF-like MARVEL transmembrane domain-containing member (CMTM) is a new gene family first cloned and reported in 2001. The CMTM family consists of nine members including CKLF and CMTM1-CMTM8, which are located on different chromosomes. Besides exhibiting extensive chemotactic activity, the CMTM family plays an important role in the hematopoiesis system, the immune system, the cardiovascular system and the male reproductive system. Recent in-depth research has also revealed that CMTM is closely associated with the genesis, development and metastasis of tumors, displaying opposing activities in diverse human tumors. In this review, we discuss the structural and functional characteristics of the CMTM family and summarize latest research findings of the relationship between several CMTM members and non-small cell lung cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Many researchers pay attention to novel secretory factors, such as adipokines or osteokines, secreted by the tissues that were not formerly recognized as classical endocrine organs. The liver also contributes to the onset of various kinds of pathologies of type 2 diabetes and obesity by producing and releasing secretory proteins "hepatokines." By using the information of gene expression in human livers, we rediscovered selenoprotein P (SeP) and leukocyte cell-derived chemotaxin 2 (LECT2) as hepatokines involved in the onset of glucose intolerance. SeP was previously recognized as a selenium transport protein, but we revealed that SeP causes insulin resistance in the muscle and liver. SeP also reduces VEGF signal transduction in vascular endothelial cells, contributing the impaired angiogenesis in diabetes. Importantly, SeP impairs health-promoting effects of exercise training by suppressing reactive oxygen species (ROS)/adenosine monophosphate-dependent protein kinase (AMPK) pathway in the skeletal muscle through its receptor low-density lipoprotein receptor-related protein 1 (LRP1). LECT2, previously-reported as a neutrophil chemotactic protein, promotes skeletal muscle insulin resistance in obesity. Further studies are necessary to develop new diagnostic or therapeutic procedures targeting hepatokines to combat type 2 diabetes or obesity.

Aims: Chemerin has been recently identified as a vasoactive adipokine implicated in blood pressure regulation. In this context, we evaluated whether chemerin could influence pulmonary vasoreactive response., Materials and Methods: Vascular reactivity to chemerin and to phenylephrine, serotonin and endothelin-1 after chemerin pretreatment was evaluated in rat isolated pulmonary artery versus thoracic aorta with and without endothelium. Vasoreactivity to acetylcholine in presence of nitric oxide (NO)-synthase inhibitor (L-NAME) and to NO donor sodium nitroprusside (SNP) was evaluated in chemerin-pretreated pulmonary artery versus thoracic aorta with endothelium. Pretreatment with ODQ, a soluble guanylate cyclase inhibitor and apocynin, a ROS production inhibitor, were also tested. Arteries and lung tissue were harvested for pathobiological evaluation., Key Findings: Chemerin contracted endothelium-denuded pulmonary artery, while no response was observed in arteries with endothelium. Chemerin potentiated phenylephrine-, endothelin-1- and serotonin-induced vasoconstriction, which was further enhanced by endothelium removal. Chemerin decreased acetylcholine-induced vasorelaxation in arteries with endothelium, while it did not affect SNP-induced relaxation. In presence of L-NAME, there remained a vasorelaxation in chemerin-pretreated arteries. Chemerin or ODQ alone partly decreased acetylcholine-induced vasorelaxation in pulmonary artery and thoracic aorta, while combined chemerin and ODQ incubation abolished it. Treatment with apocynin partly or totally reversed chemerin effects. In both types of arteries, chemerin reduced acetylcholine-induced NO production, as well as endothelial and inducible NO-synthase expression., Significance: Chemerin potentiates vascular responses to vasoconstrictors in pulmonary artery and thoracic aorta and, impairs acetylcholine-induced pulmonary artery vasodilatation, by mechanisms involving at least partly NO signaling and oxidative stress., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Abdominal aortic aneurysm (AAA) is a pathological condition of permanent vessel dilatation that predisposes to the potentially fatal consequence of aortic rupture. SGLT-2 (sodium-glucose cotransporter 2) inhibitors have emerged as powerful pharmacological tools for type 2 diabetes mellitus treatment. Beyond their glucose-lowering effects, recent studies have shown that SGLT-2 inhibitors reduce cardiovascular events and have beneficial effects on several vascular diseases such as atherosclerosis; however, the potential effects of SGLT-2 inhibition on AAA remain unknown. This study evaluates the effect of oral chronic treatment with empagliflozin-an SGLT-2 inhibitor-on dissecting AAA induced by Ang II (angiotensin II) infusion in apoE (apolipoprotein E) -/ - mice. Approach and Results: Empagliflozin treatment significantly reduced the Ang II-induced increase in maximal suprarenal aortic diameter in apoE -/ - mice independently of blood pressure effects. Immunohistochemistry analysis revealed that empagliflozin diminished Ang II-induced elastin degradation, neovessel formation, and macrophage infiltration at the AAA lesion. Furthermore, Ang II infusion resulted in a marked increase in the expression of chemokines (CCL-2 [chemokine (C-C motif) ligand 2] and CCL-5 [chemokine (C-C motif) ligand 5]), VEGF (vascular endothelial growth factor), and MMP (matrix metalloproteinase)-2 and MMP-9 in suprarenal aortic walls of apoE -/ - mice, and all were reduced by empagliflozin cotreatment. Western blot analysis revealed that p38 MAPK (p38 mitogen-activated protein kinase) and NF-κB (nuclear factor-κB) activation was also reduced in the suprarenal aortas of apoE -/ - mice cotreated with empagliflozin. Finally, in vitro studies in human aortic endothelial cells and macrophages showed that empagliflozin inhibited leukocyte-endothelial cell interactions and release of proinflammatory chemokines., Conclusions: Pharmacological inhibition of SGLT-2 by empagliflozin inhibits AAA formation. SGLT-2 inhibition might represent a novel promising therapeutic strategy to prevent AAA progression.

Background: Injection of adipose-derived mesenchymal stromal cells (ASCs) into murine knee joints after induction of inflammatory collagenase-induced osteoarthritis (CiOA) reduces development of joint pathology. This protection is only achieved when ASCs are applied in early CiOA, which is characterized by synovitis and high S100A8/A9 and IL-1β levels, suggesting that inflammation is a prerequisite for the protective effect of ASCs. Our objective was to gain more insight into the interplay between synovitis and ASC-mediated amelioration of CiOA pathology. Methods: CiOA was induced by intra-articular collagenase injection. Knee joint sections were stained with hematoxylin/eosin and immunolocalization of polymorphonuclear cells (PMNs) and ASCs was performed using antibodies for NIMP-R14 and CD271, respectively. Chemokine expression induced by IL-1β or S100A8/A9 was assessed with qPCR and Luminex. ASC-PMN co-cultures were analyzed microscopically and with Luminex for inflammatory mediators. Migration of PMNs through transwell membranes toward conditioned medium of non-stimulated ASCs (ASC NS -CM) or IL-1β-stimulated ASCs (ASC IL-1β -CM) was examined using flow cytometry. Phagocytic capacity of PMNs was measured with labeled zymosan particles. Results: Intra-articular saline injection on day 7 of CiOA increased synovitis after 6 h, characterized by PMNs scattered throughout the joint cavity and the synovium. ASC injection resulted in comparable numbers of PMNs which clustered around ASCs in close interaction with the synovial lining. IL-1β-stimulation of ASCs in vitro strongly increased expression of PMN-attracting chemokines CXCL5, CXCL7, and KC, whereas S100A8/A9-stimulation did not. In agreement, the number of clustered PMNs per ASC was significantly increased after 6 h of co-culturing with IL-1β-stimulated ASCs. Also migration of PMNs toward ASC IL-1β -CM was significantly enhanced (287%) when compared to ASC NS -CM. Interestingly, association of PMNs with ASCs significantly diminished KC protein release by ASCs (69% lower after 24 h), accompanied by reduced release of S100A8/A9 protein by the PMNs. Moreover, phagocytic capacity of PMNs was strongly enhanced after priming with ASC IL-1β -CM. Conclusions: Local application of ASCs in inflamed CiOA knee joints results in clustering of attracted PMNs with ASCs in the synovium, which is likely mediated by IL-1β-induced up-regulation of chemokine release by ASCs. This results in enhanced phagocytic capacity of PMNs, enabling the clearance of debris to attenuate synovitis.

Objective- Expression of the chemokine-like receptor ChemR23 (chemerin receptor 23) has been specifically attributed to plasmacytoid dendritic cells (pDCs) and macrophages and ChemR23 has been suggested to mediate an inflammatory immune response in these cells. Because chemokine receptors are important in perpetuating chronic inflammation, we aimed to establish the role of ChemR23-deficiency on macrophages and pDCs in atherosclerosis. Approach and Results- ChemR23-knockout/knockin mice expressing eGFP (enhanced green fluorescent protein) were generated and after crossing with apolipoprotein E-deficient ( Apoe -/- ChemR23 e/e ) animals were fed a western-type diet for 4 and 12 weeks. Apoe -/- ChemR23 e/e mice displayed reduced lesion formation and reduced leukocyte adhesion to the vessel wall after 4 weeks, as well as diminished plaque growth, a decreased number of lesional macrophages with an increased proportion of M2 cells and a less inflammatory lesion composition after 12 weeks of western-type diet feeding. Hematopoietic ChemR23-deficiency similarly reduced atherosclerosis. Additional experiments revealed that ChemR23-deficiency induces an alternatively activated macrophage phenotype, an increased cholesterol efflux and a systemic reduction in pDC frequencies. Consequently, expression of the pDC marker SiglecH in atherosclerotic plaques of Apoe -/- ChemR23 e/e mice was declined. ChemR23-knockout pDCs also exhibited a reduced migratory capacity and decreased CCR (CC-type chemokine receptor)7 expression. Finally, adoptive transfer of sorted wild-type and knockout pDCs into Apoe -/- recipient mice revealed reduced accumulation of ChemR23-deficient pDCs in atherosclerotic lesions. Conclusions- Hematopoietic ChemR23-deficiency increases the proportion of alternatively activated M2 macrophages in atherosclerotic lesions and attenuates pDC homing to lymphatic organs and recruitment to atherosclerotic lesions, which synergistically restricts atherosclerotic plaque formation and progression.

With the incidence and impact of atherosclerotic cardiovascular disease and its clinical manifestations still rising, therapeutic options that target the causal mechanisms of this disorder are highly desired. Since the CANTOS trial (Canakinumab Antiinflammatory Thrombosis Outcome Study) has demonstrated that lowering inflammation can be beneficial, focusing on mechanisms underlying inflammation, for example, leukocyte recruitment, is feasible. Being key orchestrators of leukocyte trafficking, chemokines have not lost their attractiveness as therapeutic targets, despite the difficult road to drug approval thus far. Still, innovative therapeutic approaches are being developed, paving the road towards the first chemokine-based therapeutic against inflammation. In this overview, recent developments for chemokines and for the chemokine-like factor MIF (macrophage migration inhibitory factor) will be discussed.

In most mammalian species, adult neurogenesis appears to occur only in the olfactory bulb and hippocampal dentate gyrus, where neural stem/progenitor cells exist to create new neurons. The discovery of multi-potential neural stem/progenitor cells (NPCs) in the adult brain has precipitated a novel therapeutic strategy for harnessing these endogenous cells to aid in recovery from neurodegenerative disorders. During neurodegeneration, a plethora of endogenous factors, including cytokines, chemokines, neurotransmitters, blood-derived factors, and reactive oxygen species, are released by the activation of resident microglia, astrocytes, and infiltrating peripheral macrophages. It is interesting that these endogenous factors affect the proliferation, migration, differentiation, and survival of newly generated cells involved in the incorporation of newly generated neurons into the brain's circuitry. The unique profile of these endogenous factors can vary the degree of neuroregeneration after neurodegeneration. We show that adult neurogenesis-activating signals are regulated by endogenous factors produced during neurodegeneration.

Background: Diabetes is a growing public health problem. Diabetic kidney disease (DKD) is the most prevalent chronic renal disease and the major cause of end-stage renal failure worldwide, predominantly due to the increase of Type 2 diabetes associated with obesity. The intimate mechanisms leading to the development and progression of renal injury in DKD are not well understood, but current knowledge indicates that its pathogenesis is multifactorial, where the immune response and inflammation appear to be relevant factors., Summary: This review summarizes the role of relevant inflammatory molecules and pathways that participate in the development of DKD. Likewise, we focused on the new therapeutic approaches based on anti-inflammatory effects of different drugs. Key Messages: This new pathogenic perspective of DKD as an inflammatory condition leads to novel horizons, such as the potential role of inflammatory signaling pathways and their downstream products as emerging biomarkers and promising therapeutic targets., (© 2018 S. Karger AG, Basel.)

CKLFSF is a protein family that serves as a functional bridge between chemokines and members of the transmembrane 4 superfamily (TM4SF). In the course of evolution, CKLFSF2 has evolved as two isoforms, namely CKLFSF2A and CKLFSF2B, in mice. CKLFSF2A, also known as CMTM2A and ARR19, is expressed in the testis and is important for testicular steroidogenesis. CKLFSF2B is also known to be highly expressed in the testis. In the prepubertal stage, CKLFSF2B is expressed only in Leydig cells, but it is highly expressed in haploid germ cells and Leydig cells in adult testis. CKLFSF2B is naturally processed inside the cell at its C-terminus to yield smaller proteins compared to its theoretical size of ≈25 kDa. The Cklfsf2b gene is regulated by GATA-1 and CREB protein, binding to their respective binding elements present in the 2-kb upstream promoter sequence. In addition, the overexpression of CKLFSF2B inhibited the activity of the Nur77 promoter, which consequently represses the promoter activity of Nur77-target steroidogenic genes such as P450c17, 3β-HSD, and StAR in MA-10 Leydig cells. Adenovirus-mediated overexpression of CKLFSF2B in primary Leydig cells isolated from adult mice shows a repression of steroidogenic gene expression and consequently testosterone production. Moreover, intratesticular injection of CKLFSF2B-expressing adenovirus in adult mice clearly had a repressive effect compared to the control injected with only GFP-expressing adenovirus. Altogether, these findings suggest that CKLFSF2B might be involved in the development and function of Leydig cells and regulate testicular testosterone production by fine-tuning the expression of steroidogenic genes., (Copyright © 2018 Elsevier B.V. All rights reserved.)