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Objective: Psoriatic arthritis (PsA) is known as a seronegative form of spondylarthropathy. The interleukin-36 cytokine family may have a major role in disease pathogenesis and particularly the related cutaneous manifestations. In light of our recent observations on (transient) autoantibody phenotypes neutralizing endogenous anti-inflammatory receptor antagonists (progranulin, IL-1Ra) in different inflammatory conditions, we set out to investigate the potential role of such antibodies targeting IL-36 cytokine family members in PsA and psoriasis without arthritic manifestations (Pso)., Methods: In the present study we screened for hypothetic autoantibodies against the anti-inflammatory mediators IL-36 receptor antagonist (IL-36Ra) and anti-inflammatory IL-38 in PsA, Pso and inflammatory and healthy controls. Serum samples of patients with PsA (n = 254), Pso (n = 100), systemic lupus erythematosus (SLE, n = 50), rheumatoid arthritis (RA, n = 100), ulcerative colitis (UC, n = 50), Crohn´s disease (CD, n = 50), and healthy controls (n = 237) were screened for autoantibodies against IL-36Ra and IL-38 as well as IL-36Ra levels by ELISA. Biochemical analysis for immune complexes and atypic protein isoforms as well as IL-36 signaling reporter assays were performed., Results: Anti-IL-36Ra antibodies were detected in five out of 100 (5.0 %) patients with Pso, in 12 of 254 (4.72 %) patients with PsA and in one of 50 (2 %) patients with CD, but in none of the other investigated inflammatory or healthy controls. The IL-36Ra autoantibodies belonged to the IgG1 subclass and their titers ranged between 1:200 to 1:1600. They resulted in immune-complex formation, depletion of serum IL-36Ra levels and were functional in terms of facilitating unrestricted IL-36 signaling., Conclusion: IL-36Ra autoantibodies were found in subgroups of patients with Pso and PsA and may drive respective pathology., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lorenz Thurner reports financial support was provided by Saarland University. If there are other authors, they 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. Published by Elsevier B.V.)

IL-26 is a cytokine that is crucial for the maintenance and function of the gut mucosal barrier. IL-26 signaling pathway relies on a heterodimeric receptor complex, which is composed of two distinct subunits, IL-10R2 and IL-20R1. However, there are no reports on the antibacterial immunity of IL-26 and its receptors in fish. For this purpose, in this study we identified IL-26 and its receptors IL-10R2 and IL-20R1 in Carassius cuvieri × Carassius auratus red var. (named WR-IL-26, WR-IL10R2 and WR-IL20R1, respectively). Phylogenetic analysis confirmed the conservation of these genes, with shared structural motifs similar to those found in higher vertebrates. Upon exposure to Aeromonas hydrophila, a common fish pathogen, there was a significant upregulation of WR-IL-26, WR-IL10R2 and WR-IL20R1 in the gut, indicating a potential role in the immune response to infection. A co-immunoprecipitation assay revealed that WR-IL-26 formed complexes with WR-IL10R2 and WR-IL20R1. In vivo experiments demonstrated that administration of WR-IL-26 activated the JAK1-STAT3 signaling pathway and protected the gut mucosa barrier from A. hydrophila infection. Conversely, silencing WR-IL10R2 and WR-IL20R1 via RNA interference significantly attenuated the activation of WR-IL-26-mediated JAK1-STAT3 pathway. These results provided new insights into the role of IL-26 and its receptors in the gut mucosa barrier and could offer novel therapeutic strategies for managing bacterial infections in aquaculture., Competing Interests: Declaration of competing interest 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 © 2024 Elsevier Ltd. All rights reserved.)

The generation and maintenance of memory T cells are regulated by various factors, including cytokines. Previous studies have shown that IL-27 is produced during the early acute phase of Plasmodium chabaudi chabaudi AS (Pcc) infection and inhibits the development of Th1-type memory CD4+ T cells. However, whether IL-27 acts directly on its receptor on Plasmodium-specific CD4+ T cells or indirectly via its receptor on other immune cells remains unclear. We aimed to determine the role of IL-27 receptor signaling in different immune cell types in regulating the generation and phenotype of memory CD4+ T cells during Plasmodium infection. We utilized Plasmodium-specific T-cell antigen receptor (TCR) transgenic mice, PbT-II, and Il27rα-/- mice to assess the direct and indirect effects of IL-27 signaling on memory CD4+ T-cell generation. Mice were transferred with PbT-II or Il27rα-/- PbT-II cells and infected with Pcc. Conditional knockout mice lacking the IL-27 receptor in T cells or dendritic cells were employed to discern the specific immune cell types involved in IL-27 receptor signaling. High levels of memory in PbT-II cells with Th1-shift occurred only when both PbT-II and host cells lacked the IL-27 receptor, suggesting the predominant inhibitory role of IL-27 signaling in both cell types. Furthermore, IL-27 receptor signaling in T cells limited the number of memory CD4+ T cells, while signaling in both T and dendritic cells contributed to the Th1 dominance of memory CD4+ T cells. These findings underscore the complex cytokine signaling network regulating memory CD4+ T cells during Plasmodium infection., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Japanese Society for Immunology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Inflammatory diseases that are driven by several pro-inflammatory cytokines has resulted in in the development of targeted therapies across different disease settings. Interleukin (IL)-36 cytokines have been implicated in several inflammatory diseases. In this review we describe the scientific evidence surrounding the use of the IL-36 receptor (IL-36R)-targeting antibody, spesolimab, in IL-36-mediated skin diseases: generalized pustular psoriasis (GPP), palmoplantar pustulosis (PPP), hidradenitis suppurativa, and Netherton syndrome (NS). Spesolimab, a high affinity, specific, humanized, antagonistic immunoglobulin G1 antibody, targets the IL-36R at a binding site distinct from its agonists, IL-36α/β/γ, and at least one endogenous antagonist, IL-36R antagonist. In vitro and in vivo data for spesolimab show effective inhibition of IL-36R-mediated signaling pathways, and six Phase I studies in healthy volunteers presented a favorable safety and pharmacokinetic (PK) profile, leading to the development of a clinical trial program to evaluate spesolimab in the treatment of IL-36R-mediated diseases. Six studies (including an expanded access program) have evaluated the efficacy, safety, PKs, and pharmacogenomics of spesolimab in patients with GPP flares. Spesolimab treatment of GPP flares resulted in rapid and sustained improvements in pustular and skin clearance, and clinically significant improvements in patient-reported symptoms and quality of life. Spesolimab also significantly reduces the risk of GPP flares and flare occurrence, preventing disease worsening and has a favorable safety profile. There have been three trials of spesolimab in PPP; further evaluation is needed to better define those patients who might benefit from the treatment. A trial of spesolimab in NS is ongoing, while other spesolimab trials suggest that IL-36 may only play a secondary role in the pathogenesis of atopic dermatitis. In conclusion, research into spesolimab has provided much needed insight into the role of IL-36 in the human immune system and the mechanism behind IL-36-mediated inflammatory diseases. Spesolimab provides an efficacious targeted treatment for GPP, a disease with a high unmet medical need., (© 2024 The Author(s). The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Spondylarthritides (SpA) are a group of autoinflammatory diseases affecting the spine, peripheral joints, and entheses, including axial spondyloarthritis (axSpA) and psoriatic arthritis. AxSpA has a multifactorial etiology that involves genetic predispositions, such as HLA-B27 and IL-23R. Although HLA-B27 is strongly associated with axSpA, its role remains unclear. GWAS studies have demonstrated that genetic polymorphisms related to the IL-23 pathway occur throughout the spectrum of SpA, including but not limited to axSpA and PsA. IL-23 promotes the production of IL-17, which drives inflammation and tissue damage. This pathway contributes not only to peripheral enthesitis but also to spinal inflammation. γδ T cells in axSpA express IL-23R and RORγt, crucial for their activation, although specific pathogenic cells and factors remain elusive. Despite drug efficacy in PsA, IL-23R inhibition is ineffective in axSpA. Murine models provide valuable insights into the intricate cellular and molecular interactions that contribute to the development and progression of SpA. Those models are useful tools to elucidate the dynamics of γδ T cell involvement, offering insights into disease mechanisms and potential therapeutic targets. This review aims to illuminate the complex interplay between IL-23 and γδ T cells in SpA pathogenesis, emphasizing their roles in chronic inflammation, tissue damage, and disease heterogeneity., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Bullous pemphigoid (BP), an autoimmune bullous dermatosis, occurs predominantly in older individuals. Nemolizumab, a humanized monoclonal antibody against the interleukin (IL)-31 receptor A, is used to treat severe atopic dermatitis (AD) in Japan. However, it can cause several adverse events, such as exacerbation of AD, erythema, and eosinophilia. Herein, we describe a case of prurigo-type AD developing BP after nemolizumab administration. A 62-year-old man with prurigo-type AD and asthma presented with serious, refractory itching. After nemolizumab injection, his pruritus was relieved for 2 days. However, on day 3, erythema with blisters and erosions suddenly appeared throughout his body. Pathological examination showed typical BP and the patient's serum anti-BP180-NC16a antibody level was 882.5 U/mL. Oral prednisolone (PSL) was initiated and nemolizumab was never used again. Despite high-dose PSL, new blisters continued to develop, with a rapid elevation of anti-BP180-NC16a antibodies to 6930 U/mL. Adding high-dose cyclosporine and intravenous gamma globulin reduced new blister formation after 9 weeks, and PSL and cyclosporine were gradually tapered. Dupilumab, an anti-IL-4 receptor antibody, was initiated after 16 weeks, resulting in continued remission without PSL and cyclosporine. The sudden occurrence of BP in this case suggested that the patient had occult BP before the nemolizumab initiation and that nemolizumab exacerbated BP and made it overt. Blocking the IL-31 pathway may exacerbate inflammation in AD or BP, resulting in the acceleration of blister formation. This may be countered by blocking the IL-4/13 pathway with dupilumab. To our knowledge, this is the first case of nemolizumab-exacerbated BP., (© 2024 Japanese Dermatological Association.)

Oropharyngeal candidiasis (OPC) is the most common human fungal infection, arising typically from T cell immune impairments. IL-17 and IL-22 contribute individually to OPC responses, but here we demonstrate that the combined actions of both cytokines are essential for resistance to OPC. Mice lacking IL-17RA and IL-22RA1 exhibited high fungal loads in esophagus- and intestinal tract, severe weight loss, and symptoms of colitis. Ultimately, mice succumbed to infection. Dual loss of IL-17RA and IL-22RA impaired expression of small proline rich proteins (SPRRs), a class of antimicrobial effectors not previously linked to fungal immunity. Sprr2a1 exhibited direct candidacidal activity in vitro, and Sprr1-3a-/- mice were susceptible to OPC. Thus, cooperative actions of Type 17 cytokines mediate oral mucosal anti-Candida defenses and reveal a role for SPRRs., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Aggor 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.)

Sjögren's disease (SjD) is a chronic autoimmune disease characterized by focal lymphocytic inflammation in lacrimal and salivary glands. We recently identified IL-27 as a requisite signal for the spontaneous SjD-like manifestations in nonobese diabetic (NOD) mice. Here, we define T cell-intrinsic effects of IL-27 in lacrimal gland disease in NOD mice. IL-27 receptor was required by both CD4 T effector (Te) cells and CD8 T cells to mediate focal inflammation. Intrinsic IL-27 signaling was associated with PD-1 and ICOS expressing T follicular helper (Tfh)-like CD4 Te cells within lacrimal glands, including subsets defined by CD73 or CD39 expression. CD8 T cells capable of IL-27 signaling also expressed PD-1 with subsets expressing ICOS and CD73 demonstrating a T follicular cytotoxic (Tfc)-like cell phenotype and others expressing a CD39 hi exhausted-like phenotype. These findings suggest IL-27 is a key early signal driving a follicular-type response in lacrimal gland inflammation in NOD mice., Competing Interests: Declaration of competing interest All authors declare that no conflicts of interest exist., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Group 3 innate lymphoid cells (ILC3s) regulate inflammation and tissue repair at mucosal sites, but whether these functions pertain to other tissues-like the kidneys-remains unclear. Here, we observed that renal fibrosis in humans was associated with increased ILC3s in the kidneys and blood. In mice, we showed that CXCR6 + ILC3s rapidly migrated from the intestinal mucosa and accumulated in the kidney via CXCL16 released from the injured tubules. Within the fibrotic kidney, ILC3s increased the expression of programmed cell death-1 (PD-1) and subsequent IL-17A production to directly activate myofibroblasts and fibrotic niche formation. ILC3 expression of PD-1 inhibited IL-23R endocytosis and consequently amplified the JAK2/STAT3/RORγt/IL-17A pathway that was essential for the pro-fibrogenic effect of ILC3s. Thus, we reveal a hitherto unrecognized migration pathway of ILC3s from the intestine to the kidney and the PD-1-dependent function of ILC3s in promoting renal fibrosis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Although inflammatory mechanisms driving hepatocellular carcinoma (HCC) have been proposed, the regulators of anticancer immunity in HCC remain poorly understood. We found that IL27 receptor (IL27R) signaling promotes HCC development in vivo. High IL27EBI3 cytokine or IL27RA expression correlated with poor prognosis for patients with HCC. Loss of IL27R suppressed HCC in vivo in two different models of hepatocarcinogenesis. Mechanistically, IL27R sig-naling within the tumor microenvironment restrains the cytotoxicity of innate cytotoxic lymphocytes. IL27R ablation enhanced their accumulation and activation, whereas depletion or functional impairment of innate cytotoxic cells abrogated the effect of IL27R disruption. Pharmacologic neutralization of IL27 signaling increased infiltration of innate cytotoxic lymphocytes with upregulated cytotoxic molecules and reduced HCC development. Our data reveal an unexpected role of IL27R signaling as an immunologic checkpoint regulating innate cytotoxic lymphocytes and promoting HCC of different etiologies, thus indicating a therapeutic potential for IL27 pathway blockade in HCC., Significance: HCC, the most common form of liver cancer, is characterized by a poor survival rate and limited treatment options. The discovery of a novel IL27-dependent mechanism controlling anticancer cytotoxic immune response will pave the road for new treatment options for this devastating disease. This article is highlighted in the In This Issue feature, p. 1825., (©2022 American Association for Cancer Research.)

Due to the plasticity of IL-17-producing CD4 T cells (Th17 cells), a long-standing challenge in studying Th17-driven autoimmune is the lack of specific surface marker to identify the pathogenic Th17 cells in vivo . Recently, we discovered that pathogenic CD4 T cells were CXCR6 positive in experimental autoimmune encephalomyelitis (EAE), a commonly used Th17-driven autoimmune model. Herein, we further revealed that peripheral CXCR6 + CD4 T cells contain a functionally distinct subpopulation, which is CCR6 positive and enriched for conventional Th17 molecules (IL-23R and RORγt) and cytotoxic signatures. Additionally, spinal cord-infiltrating CD4 T cells were highly cytotoxic by expressing Granzyme(s) along with IFNγ and GM-CSF. Collectively, this study suggested that peripheral CCR6 + CXCR6 + CD4 T cells were Th17 cells with cytotoxic property in EAE model, and highlighted the cytotoxic granzymes for EAE pathology., Competing Interests: Author LH is a cofounder and shareholder of Edelweiss Immune Inc. Both authors declare that the research was conducted in the absence of any other commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hou and Yuki.)

Interleukin-23 (IL-23) is a pro-inflammatory cytokine involved in the host defense against pathogens but is also implicated in the development of several autoimmune disorders. The IL-23 receptor has become a key target for drug discovery, but the exact mechanism of the receptor ligand interaction remains poorly understood. In this study the affinities of IL-23 for its individual receptor components (IL23R and IL12Rβ1) and the heteromeric complex formed between them have been measured in living cells using NanoLuciferase-tagged full-length proteins. Here, we demonstrate that TAMRA-tagged IL-23 has a greater than 7-fold higher affinity for IL12Rβ1 than IL23R. However, in the presence of both receptor subunits, IL-23 affinity is increased more than three orders of magnitude to 27 pM. Furthermore, we show that IL-23 induces a potent change in the position of the N-terminal domains of the two receptor subunits, consistent with a conformational change in the heteromeric receptor structure., Competing Interests: Declaration of interests P.D.C, A.B., and Z.S. are employees of and shareholders in GSK., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Pruritus is a common dermatological condition and negatively impacts QOL. Persistent pruritus and excessive scratching behavior can lead to the itch-scratch cycle that exacerbates inflammatory skin diseases. Conventional antipruritic drugs, such as antihistamines, corticosteroids, or anticonvulsants, are sometimes insufficient. Recently, however, molecularly targeted drugs, such as IL-31 or IL-4 receptor-targeting antibodies, have become available or are under clinical trials, dramatically changing the clinical situation. In fact, some of these drugs can improve pruritus without the need for topical steroids. Taken together, these observations point to the importance of cytokine-mediated pruritus, further understanding of which may guide improved therapies., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

IL-12 (p35/p40) and IL-23 (p19/p40) signal through IL-12R (IL-12Rβ2/β1) and IL-23R (IL-23Rα/IL-12Rβ1), respectively, which can promote pathogenic T lymphocyte activation, differentiation, and function in graft-versus-host disease (GVHD). With the use of murine models of allogeneic hematopoietic cell transplantation (HCT), we found that IL-12Rβ1 on donor T cells was dispensable to induce acute GVHD development in certain circumstances, while IL-23Rα was commonly required. This observation challenges the current paradigm regarding IL-12Rβ1 as a prerequisite to transmit IL-23 signaling. We hypothesized that p19/EBI3 (IL-39) may have an important role during acute GVHD. With the use of gene transfection and immunoprecipitation approaches, we verified that p19 and EBI3 can form biological heterodimers. We found that IL-39 levels in recipient serum positively correlated with development of acute GVHD in experimental models and in clinical settings, thereby implicating IL-39 in the pathogenesis of acute GVHD. Furthermore, we observed that human T cells can signal in response to IL-39. In chronic GVHD, IL-23Rα and IL-12Rβ1 were similarly required for donor T cell pathogenicity, and IL-39 levels were not significantly different from controls without GVHD. Collectively, we identify a novel cytokine, IL-39, as a pathogenic factor in acute GVHD, which represents a novel potential therapeutic target to control GVHD and other inflammatory disorders., (© 2021 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Systemic sclerosis (SSc) is a chronic multisystem disorder characterized by fibrosis and autoimmunity. Interleukin (IL)-31 has been implicated in fibrosis and T helper (Th) 2 immune responses, both of which are characteristics of SSc. The exact role of IL-31 in SSc pathogenesis is unclear. Here we show the overexpression of IL-31 and IL-31 receptor A (IL-31RA) in dermal fibroblasts (DFs) from SSc patients. We elucidate the dual role of IL-31 in SSc, where IL-31 directly promotes collagen production in DFs and indirectly enhances Th2 immune responses by increasing pro-Th2 cytokine expression in DFs. Furthermore, blockade of IL-31 with anti-IL-31RA antibody significantly ameliorates fibrosis and Th2 polarization in a mouse model of SSc. Therefore, in addition to defining IL-31 as a mediator of fibrosis and Th2 immune responses in SSc, our study provides a rationale for targeting the IL-31/IL-31RA axis in the treatment of SSc., (© 2021. The Author(s).)

Group 2 innate lymphoid cells (ILC2s) play an important role in the pathophysiology of asthma via the robust production of type 2 cytokines. Recent studies have demonstrated that TLR7 (Toll-like receptor 7) signaling skews toward a type 1 inflammatory response in asthma, which may lead to the development of novel treatment strategies. However, the effect of TLR7 signaling on ILC2-dependent nonallergic eosinophilic inflammation remains unclear. In this study, we investigated the effects of R848, a TLR7 agonist, in a mouse model of IL-33-induced eosinophilic airway inflammation. Intranasal administration of R848 decreased infiltration of airway eosinophils and ILC2s, mucus production in epithelial cells, and type 2 cytokine production. Flow cytometric analysis identified an increased number of interstitial macrophages (IMs) expressing a high level of TLR7 in the lung upon IL-33 stimulation. IL-33-induced IMs also expressed high levels of alternatively activated (M2)-type genes and chemokines (CCL17 and CCL24). However, R848 stimulation modified these gene expressions and elicited the production of IL-27. Coculture experiments revealed that IL-33-induced IMs directly suppressed ILC2 activation in response to R848. In addition, the inhibitory effects of R848 on ILC2-induced type 2 inflammation were defective in WSX-1-deficient mice lacking the IL-27 receptor. Taken together, these findings indicate that R848 stimulates IL-33-induced IMs to suppress ILC2-mediated type 2 airway inflammation via IL-27. These findings highlight the therapeutic potential of TLR7 agonists and/or IL-27 cascades in nonallergic asthma.

Purpose of the Study: The involvement of the IL-23/IL23R pathway is well known in the disease pathogenesis of sarcoidosis and other inflammatory diseases. To date, the pathogenic mechanism of IL-23 is most notably described on CD4 + Th17 lymphocytes. However, the function of the IL23R on myeloid cells in sarcoidosis is poorly understood. Thus, the aim of the study is to investigate the role of the IL23R on myeloid cell in pulmonary granuloma formation. Methods: We generated IL23RLysMCre mice lacking the IL23R gene in myeloid cells. The importance of IL23R in myeloid cells for the development of sarcoidosis was studied in a mouse model of inflammatory lung granuloma formation through embolization of PPD from Mycobacterium bovis -coated Sepharose beads into previously PPD-immunized mice. In addition the function of IL23R on myeloid cells was studied in LPS or IFNγ stimulated BMDMs and BMDCs. The mRNA and protein expression levels of relevant cytokines were analyzed by RT-PCR (TaqMan) and ELISA. The composition of immune cells in BALF was quantified by flow cytometry and alteration in granuloma sizes were observed by H&E stained lung sections. Results: Mycobacterium Ag-elicted pulmonary granulomas tend to be smaller in IL23RLysMCre mice and NF-κB dependent Th1 cytokines in the murine lungs are reduced compared to wildtype mice. In line, we observed that IL23R-deficient bone marrow-derived macrophages show a reduced production of Th1 cytokines after LPS stimulation. Conclusion: We here for the first time demonstrate a role for IL23R on myeloid cells in pulmonary inflammation and granuloma formation. Our findings provide essential insights in the pathogenesis of inflammatory lung diseases like sarcoidosis, which might be useful for the development of novel therapeutics targeting distinct immunological pathways like IL-23/IL23R.

Interleukins (ILs) and interleukin receptors (ILRs) play important role in the antitumor immune response. However, the expression signature and clinical characteristics of the IL(R) family in lung adenocarcinoma (LUAD) remains unclear. The main purpose of this study was to explore the expression profile of IL(R) family genes and construct an IL(R)-based prognostic signature in LUAD. Five public datasets of 1,312 patients with LUAD were enrolled in this study. Samples from The Cancer Genome Atlas (TCGA) were used as the training set, and samples from the other four cohorts extracted from Gene Expression Omnibus (GEO) database were used as the validation set. Additionally, the profile of IL(R) family signature was explored, and the association between this signature and immunotherapy response was also analyzed. Meanwhile, the prognostic value was compared between this IL(R)-based signature and different immunotherapy markers. A signature based on five identified IL(R)s (IL7R, IL5RA, IL20RB, IL11, IL22RA1) was constructed using the TCGA dataset through univariate/multivariable Cox proportional hazards regression and least absolute shrinkage and selection operator (LASSO) Cox analysis. These cases with LUAD were stratified into high- and low-risk group according to the risk score. This signature showed a strong prognostic ability, which was verified by the five independent cohorts and clinical subtypes. The IL(R)-based models presented unique characteristics in terms of immune cell infiltration and immune inflammation profile in tumor microenvironment (TME). Biological pathway analysis confirmed that high-risk patients showed significant T- and B-cell immunosuppression and rapid tumor cell proliferation. More importantly, we researched the relationship between this IL(R)-based signature and immune checkpoints, tumor mutation burden (TMB), tumor purity and ploidy, and tumor immune dysfunction and exclusion (TIDE) score, which confirmed that this signature gave the best prognostic value. We first provided a robust prognostic IL(R)-based signature, which had the potential as a predictor for immunotherapy response to realize individualized treatment of LUAD., 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 Fan, Pan, Yang, Hao, Zhang, Li and Geng.)

The IL-23/IL-17 axis plays causative roles in the development and progression of systemic lupus erythematosus (SLE). However, it remains unclear if the IL-17RA + and IL-23R + T helper (Th) cells populations are associated with the serum IL-17 and IL-23 levels, or with the immunological parameters and disease activities in SLE patients. Herein, we examined the proportion of IL-17RA + and IL-23R + Th cells and serum levels of IL-17 and IL-23 in established SLE patients (n = 50) compared with healthy controls (n = 50). The associations of these interleukins and their receptors with immunological parameters [anti-nuclear antibody (ANA), anti-dsDNA antibody, and C-reactive protein (CRP)] and SLE disease activity (SLEDAI-2K scores) in SLE patients were assessed. CD3 + CD4 + Th cells of SLE patients demonstrated significantly elevated IL-17RA + ( p = 1.12 x 10 -4 ) or IL-23R + ( p  = 1.98 x 10 -29 ) populations compared with the healthy controls. Serum IL-17 levels were significantly lower in SLE patients compared with the healthy controls ( p = 8.32 x 10 -5 ), while no significant difference was observed for the IL-23 serum levels between both groups. IL-23R + Th cells population was significantly associated with higher SLEDAI-2K scores ( p  = 0.017). In multivariate analysis, the proportion of IL-23R + Th cells remained significantly associated with higher SLEDAI-2K scores independent of prednisolone intake ( p = 0.027). No associations were observed between the interleukin parameters (i.e., IL-17, IL-23, IL-17RA + Th cells, and IL-23R + Th cells) with ANA, anti-dsDNA, and CRP status, suggesting that the IL-17/IL-23 axis acts independently of these immunological parameters. In conclusion, our results support that therapeutic inhibition of the IL-23/IL-17 axis receptors on Th cells, particularly IL-23R, is potentially relevant in SLE patients., 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 Izati, Mohd Shukri, Wan Ghazali, Che Hussin and Wong.)

Enhancer RNAs (eRNAs) are a subclass of non-coding RNAs that are generated during the transcription of enhancer regions and play an important role in tumourigenesis. In this study, we focused on the crucial eRNAs that participate in immune responses in invasive breast cancer (IBC). We first used The Cancer Genome Atlas and Human enhancer RNA Atlas to screen for tissue-specific eRNAs and their target genes. Through Pearson correlation analysis with immune genes, the eRNA WAKMAR2 was identified as a key candidate involved in IBC. Our further research suggested that WAKMAR2 is crucial in regulating the tumour microenvironment and may function by regulating immune-related genes, including IL27RA, RAC2, FABP7, IGLV1-51, IGHA1, and IGHD. Quantitative reverse transcription-polymerase chain reaction was used to detect the expression of WAKMAR2 in IBC and normal tissues, and the effect of WAKMAR2 on the regulation of downstream genes in MB-231 and MCF7 cells was studied in vitro. WAKMAR2 was found to be highly involved in tumour immunity and was downregulated in IBC tissues. Furthermore, the expression of WAKMAR2 and its target genes was observed at the pan-cancer level. This study provides evidence to suggest new potential targets for the treatment of breast cancer., (© 2021. The Author(s).)

Inflammatory monocyte-derived dendritic cells (Mo-DCs) have been described in several chronic inflammatory disorders, such as rheumatoid arthritis (RA), and are suspected to play a detrimental role by fueling inflammation and skewing adaptive immune responses. However, the characterization of their phenotype is still limited, as well as the comprehension of the factors that govern their differentiation. Here, we show that inflammatory Mo-DCs generated in vitro expressed a large and atypical panel of C-type lectin receptors, including isoforms of CD209 and CD206, CD303 and CD207, as well as intracellular proteins at their surfaces such as the lysosomal protein CD208. Combination of these markers allowed us to identify cells in the synovial fluid of RA patients with a close phenotype of inflammatory Mo-DCs generated in vitro. Finally, we found in coculture experiments that RA synoviocytes critically affected the phenotypic differentiation of monocytes into Mo-DCs, suggesting that the crosstalk between infiltrating monocytes and local mesenchymal cells is decisive for Mo-DCs generation.

Necrotizing enterocolitis (NEC) is a deadly intestinal inflammatory disorder that primarily affects premature infants and lacks adequate therapeutics. Interleukin (IL)-22 plays a critical role in gut barrier maintenance, promoting epithelial regeneration, and controlling intestinal inflammation in adult animal models. However, the importance of IL-22 signaling in neonates during NEC remains unknown. We investigated the role of IL-22 in the neonatal intestine under homeostatic and inflammatory conditions by using a mouse model of NEC. Our data reveal that Il22 expression in neonatal murine intestine is negligible until weaning, and both human and murine neonates lack IL-22 production during NEC. Mice deficient in IL-22 or lacking the IL-22 receptor in the intestine display a similar susceptibility to NEC, consistent with the lack of endogenous IL-22 during development. Strikingly, treatment with recombinant IL-22 during NEC substantially reduces inflammation and enhances epithelial regeneration. These findings may provide a new therapeutic strategy to attenuate NEC., Competing Interests: Drs. J.K.K. and M. Good have a patent pending on the use of IL-22 to prevent or treat NEC. Dr. M. Good has received sponsored research agreement funding from Astarte Medical, Evive Biotech, and Takeda Pharmaceuticals. Dr. M. Good also serves on the Scientific Advisory Council of the NEC Society and the Clinical and Technology Advisory Board of Astarte Medical. She also participated in a neonatal microbiome advisory board for Abbott Laboratories in 2019. None of these sources had any role in this study., (© 2021 The Author(s).)

Low-grade inflammatory monocytes critically contribute to the pathogenesis of chronic inflammatory diseases such as atherosclerosis. The elevated expression of coactivating molecule CD40 as well as key adhesion molecule CD11a is a critical signature of inflammatory monocytes from both human patients with coronary artery diseases as well as in animal models of atherosclerosis. In this study, we report that subclinical superlow-dose LPS, a key risk factor for low-grade inflammation and atherosclerosis, can potently trigger the induction of CD40 and CD11a on low-grade inflammatory monocytes. Subclinical endotoxin-derived monocytes demonstrate immune-enhancing effects and suppress the generation of regulatory CD8 + CD122 + T cells, which further exacerbate the inflammatory environment conducive for chronic diseases. Mechanistically, subclinical endotoxemia activates TRAM-mediated signaling processes, leading to the activation of MAPK and STAT5, which is responsible for the expression of CD40 and CD11a. We also demonstrate that TRAM-mediated monocyte polarization can be suppressed by IRAK-M. IRAK-M-deficient monocytes have increased expression of TRAM, elevated induction of CD40 and CD11a by subclinical-dose endotoxin, and are more potent in suppressing the CD8 regulatory T cells. Mice with IRAK-M deficiency generate an increased population of inflammatory monocytes and a reduced population of CD8 T regulatory cells. In contrast, mice with TRAM deficiency exhibit a significantly reduced inflammatory monocyte population and an elevated CD8 T regulatory cell population. Together, our data reveal a competing intracellular circuitry involving TRAM and IRAK-M that modulate the polarization of low-grade inflammatory monocytes with an immune-enhancing function., (Copyright © 2021 by The American Association of Immunologists, Inc.)

WSX1, a receptor subunit for IL-27, is widely expressed in immune cells and closely involved in immune response, but its function in nonimmune cells remains unknown. Here we report that WSX1 is highly expressed in human hepatocytes but downregulated in hepatocellular carcinoma (HCC) cells. Using NRAS/AKT-derived spontaneous HCC mouse models, we reveal an IL-27-independent tumor-suppressive effect of WSX1 that largely relies on CD8 + T-cell immune surveillance via reducing neoplastic PD-L1 expression and the associated CD8 + T-cell exhaustion. Mechanistically, WSX1 transcriptionally downregulates an isoform of PI3K-PI3Kδ and thereby inactivates AKT, reducing AKT-induced GSK3β inhibition. Activated GSK3β then boosts PD-L1 degradation, resulting in PD-L1 reduction. Overall, we demonstrate that WSX1 is a tumor suppressor that reinforces hepatic immune surveillance by blocking the PI3Kδ/AKT/GSK3β/PD-L1 pathway. Our results may yield insights into the host homeostatic control of immune response and benefit the development of cancer immunotherapies.

In chronic Chagas disease, Trypanosoma cruzi-specific T-cell function decreases over time, and alterations in the homeostatic IL-7/IL-7R axis are evident, consistent with a process of immune exhaustion. IL-27 is an important immunoregulatory cytokine that shares T-cell signaling with IL-7 and other cytokines of the IL-12 family and might be involved in the transcriptional regulation of T-cell function. Here, we evaluated the expression and function of IL-27R in antigen-experienced T cells from subjects with chronic Chagas disease and assessed whether in vitro treatment with IL-27 and IL-7 might improve T. cruzi-specific polyfunctional T-cell responses. In vitro exposure of PBMCs to T. cruzi induced a downregulation of IL-27R in CD4+ T cells and an upregulation in CD8+ T cells in subjects without heart disease, while IL-27R expression remained unaltered in subjects with more severe clinical stages. The modulation of IL-27R was associated with functional signaling through STAT3 and STAT5 and induction of the downstream genes TBX21, EOMES and CXCL9 in response to IL-27. In vitro treatment of PBMCs with IL-27 and IL-7 improved monofunctional and polyfunctional Th1 responses, accompanied by the induction of IL-10 and Bcl-2 expression in subjects without heart disease but did not improve those in subjects with cardiomyopathy. Our findings support the process of desensitization of the IL-27/IL-27R pathway along with disease severity and that the pro-inflammatory and immunomodulatory mechanisms of IL-27 might be interconnected., Competing Interests: The authors have declared that no competing interests exist.

IL-27, a heterodimeric cytokine of the IL-12 family, has diverse influences on the development of multiple inflammatory diseases. In this study, we identified the protective role of IL-27/IL-27R in host defense against Chlamydia muridarum respiratory infection and further investigated the immunological mechanism. Our results showed that IL-27 was involved in C. muridarum infection and that IL-27R knockout mice (WSX-1 -/- mice) suffered more severe disease, with greater body weight loss, higher chlamydial loads, and more severe inflammatory reactions in the lungs than C57BL/6 wild-type mice. There were excessive IL-17-producing CD4 + T cells and many more neutrophils, neutrophil-related proteins, cytokines, and chemokines in the lungs of WSX-1 -/- mice than in wild-type mice following C. muridarum infection. In addition, IL-17/IL-17A-blocking Ab treatment improved disease after C. muridarum infection in WSX-1 -/- mice. Overall, we conclude that IL-27/IL-27R mediates protective immunity during chlamydial respiratory infection in mice by suppressing excessive Th17 responses and reducing neutrophil inflammation., (Copyright © 2021 by The American Association of Immunologists, Inc.)

Tumor necrosis factor (TNF)/inducible nitric oxide synthase (iNOS)-producing dendritic cells (Tip-DCs) have profound impacts on host immune responses during infections. The mechanisms regulating Tip-DC development remain largely unknown. Here, using a mouse model of infection with African trypanosomes, we show that a deficiency in interleukin-27 receptor (IL-27R) signaling results in escalated intrahepatic accumulation of Ly6C-positive (Ly6C + ) monocytes and their differentiation into Tip-DCs. Blocking Tip-DC development significantly ameliorates liver injury and increases the survival of infected IL-27R -/- mice. Mechanistically, Ly6C + monocyte differentiation into pathogenic Tip-DCs in infected IL-27R -/- mice is driven by a CD4 + T cell-interferon gamma (IFN-γ) axis via cell-intrinsic IFN-γ signaling. In parallel, hyperactive IFN-γ signaling induces cell death of Ly6C-negative (Ly6C - ) monocytes in a cell-intrinsic manner, which in turn aggravates the development of pathogenic Tip-DCs due to the loss of the negative regulation of Ly6C - monocytes on Ly6C + monocyte differentiation into Tip-DCs. Thus, IL-27 inhibits the dual-track exacerbation of Tip-DC development induced by a CD4 + T cell-IFN-γ axis. We conclude that IL-27 negatively regulates Tip-DC development by preventing the cell-intrinsic effects of IFN-γ and that the regulation involves CD4 + T cells and Ly6C - monocytes. Targeting IL-27 signaling may manipulate Tip-DC development for therapeutic intervention. IMPORTANCE TNF/iNOS-producing dendritic cells (Tip-DCs) are at the front line as immune effector cells to fight off a broad range of invading microbes. Excessive development of Tip-DCs contributes to tissue destruction. Thus, identifying master regulators of Tip-DC development is fundamental for developing new therapeutic strategies. Here, we identify Tip-DCs as a terminal target of IL-27, which prevents Tip-DC-mediated early mortality during parasitic infections. We demonstrate that IL-27 inhibits Tip-DC development via a dual-track mechanism involving the complex interactions of effector CD4 + T cells, Ly6C - monocytes, and Ly6C + monocytes. These findings delineate an in-depth view of mechanisms of Tip-DC differentiation that may have significant implications for the ongoing development of IL-27-based immunotherapy., (Copyright © 2021 Liu et al.)

Background: Interleukin (IL)-35 and IL-35-producing regulatory T cells (iTr35) have been reported to inhibit T H 2 response in allergic rhinitis (AR). However, its effects on type II innate lymphoid cells (ILC2) are not well characterized., Objective: To investigate the effect of IL-35 on ILC2 in AR., Methods: A total of 25 patients with AR and 20 controls were recruited. The expression and regulation of IL-35 receptor in ILC2 were analyzed by real-time polymerase chain reaction. The effect of IL-35 on ILC2 differentiation and cytokine production was analyzed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. In addition, iTr35 were cocultured with ILC2 to explore the effect of iTr35 on ILC2. The AR mice models were also established to confirm the role of IL-35 in vivo., Results: The patients with AR had decreased IL-35 expression and iTr35 proportion and increased ILC2 and type II cytokines compared with the controls. Notably, IL-35 inhibited ILC2 differentiation and type II cytokine production by regulating IL-12Rβ2 and gp130. IL-35 promoted the inducible costimulatory molecule expression by iTr35 and the inducible costimulatory molecule ligand expression by ILC2. IL-35-treated mice with AR presented decreased frequency and function of nasal ILC2., Conclusion: IL-35 inhibited ILC2 responses directly or through mutual contact between iTr35 and ILC2 in AR, suggesting that IL-35 may be used as a potential treatment target in AR., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Interleukin-31 (IL-31) is a Th2 cell-derived cytokine that has been closely linked to pruritic skin inflammation. More recently, enhanced IL-31 serum levels have also been observed in patients with allergic rhinitis and allergic asthma. Therefore, the main aim of this study was to unravel the contribution of IL-31 to allergen-induced lung inflammation. We analyzed lung inflammation in response to the timothy grass (Phleum pratense) pollen allergen Phl p 5 in C57BL/6 wild-type (wt) mice, IL-31 transgenic (IL-31tg) mice, and IL-31 receptor alpha-deficient animals (IL-31RA -/- ). IL-31 and IL-31RA levels were monitored by qRT-PCR. Cellular infiltrate in bronchoalveolar lavage fluid (BALF) and lung tissue inflammation, mucus production as well as epithelial thickness were measured by flow cytometry and histomorphology. While allergen challenge induced IL-31RA expression in lung tissue of wt and IL-31tg mice, high IL-31 expression was exclusively observed in lung tissue of IL-31tg mice. Upon Phl p 5 challenge, IL-31tg mice showed reduced numbers of leukocytes and eosinophils in BALF and lung tissue as well as diminished mucin expression and less pronounced epithelial thickening compared to IL-31RA -/- or wt animals. These findings suggest that the IL-31/IL-31RA axis may regulate local, allergen-induced inflammation in the lungs., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Breast cancer (BC) poses one of the major threats to female's health worldwide. Immune infiltration in BC is a key representative of the tumor microenvironment and has been proven highly relevant for prognosis. The role of the FREM1 (FRAS1-Related Extracellular Matrix 1) gene in carcinoma has not studied, moreover, the underlying mechanism remains largely unknown. This study aims to investigate the expression profile and potential action of FREM1 on BC progression. We applied series of bioinformatic methods as well as immunohistochemistry (IHC) and immunofluorescence (IF) to analyze FREM1 expression profile, its relationship with clinicopathological characteristics, impact on clinical outcomes, relevant functions, correlation with immune infiltration in BC. The results demonstrated that FREM1 had a dramatically reduced expression in BC tissues, possessed an inverse correlation with stage, age, and metastasis, and exhibited a higher level in invasive lobular breast carcinoma than in ductal one. Furthermore, decreased FREM1 expression was often associated with estrogen receptor (ER)/progesterone receptor (PR) negative and triple negative breast carcinoma (TNBC) status while human epidermal growth factor 2 (Her-2) positive status, and considerably correlated with a worse overall survival (OS) and recurrence-free survival (RFS). Meanwhile, the univariate/multivariate Cox model revealed that low-FREM1 expression can be an independent prognostic factor for BC. Additionally, FREM1 was mainly involved in the cell metabolism and immune cells infiltration. Moreover, IHC and IF demonstrated a positive correlation of its expression with the immune infiltrating levels of CD4 + , CD8 + T cells, and CD86 + M1 macrophages while a negative correlation with CD68 + pan-macrophages and CD163 + M2 macrophages. These findings suggest that FREM1 can be a potential biomarker for evaluating the immune infiltrating status, and the BC prognosis., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Epstein-Barr virus-induced gene 3 (EBI3) is a subunit common to IL-27, IL-35, and IL-39. Here, we explore an intracellular role of EBI3 that is independent of its function in cytokines. EBI3-deficient naive CD4+ T cells had reduced IFN-γ production and failed to induce T cell-dependent colitis in mice. Similarly reduced IFN-γ production was observed in vitro in EBI3-deficient CD4+ T cells differentiated under pathogenic Th17 polarizing conditions with IL-23. This is because the induction of expression of one of the IL-23 receptor (IL-23R) subunits, IL-23Rα, but not another IL-23R subunit, IL-12Rβ1, was selectively decreased at the protein level, but not the mRNA level. EBI3 augmented IL-23Rα expression via binding to the chaperone molecule calnexin and to IL-23Rα in a peptide-dependent manner, but not a glycan-dependent manner. Indeed, EBI3 failed to augment IL-23Rα expression in the absence of endogenous calnexin. Moreover, EBI3 poorly augmented the expression of G149R, an IL-23Rα variant that protects against the development of human colitis, because binding of EBI3 to the variant was reduced. Taken together with the result that EBI3 expression is inducible in T cells, the present results suggest that EBI3 plays a critical role in augmenting IL-23Rα protein expression via calnexin under inflammatory conditions.

Objectives: Cytokines released by infiltrating T cells may promote mechanisms leading to fibrosis in scleroderma. The aim of this study was to investigate the role of the Th2 cytokine IL-31, and its receptor IL-31RA, in scleroderma skin and lung fibrosis., Methods: IL-31 was measured by ELISA of plasma, and by immunochemistry of fibrotic skin and lung tissue of scleroderma patients. The receptor, IL-31RA, was assayed by qPCR of tissue resident cells. Next-generation sequencing was used to profile the responses of normal skin fibroblasts to IL-31. In wild-type Balb/c mice, IL-31 was administered by subcutaneous mini pump, with or without additional TGFβ, and the fibrotic reaction measured by histology and ELISA of plasma., Results: IL-31 was present at high levels in plasma and fibrotic skin and lung lesions in a subset of scleroderma patients, and the receptor overexpressed by downstream cells relevant to the disease process, including skin and lung fibroblasts, through loss of epigenetic regulation by miR326. In skin fibroblasts, IL-31 induced next generation sequencing profiles associated with cellular growth and proliferation, anaerobic metabolism and mineralization, and negatively associated with angiogenesis and vascular repair, as well as promoting phenotype changes including migration and collagen protein release via pSTAT3, resembling the activation state in the disease. In mice, IL-31 induced skin and lung fibrosis. No synergy was seen with TGFβ, which supressed IL-31RA., Conclusion: IL-31/IL-31RA is confirmed as a candidate pro-fibrotic pathway, which may contribute to skin and lung fibrosis in a subset of scleroderma patients., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Cryptococcal meningitis is one of the most common life-threatening diseases caused by Cryptococcus infection. Increasing evidence indicates that type 2 immunity is associated with disease progression by promoting fungal growth and dissemination. However, factors that govern this pathogenic response during infection are still elusive. In this study, we investigated the role of IL-25, one of the type 2-inducing cytokines produced by epithelial cells, in contributing to the pathogenesis of cryptococcosis. We found that pulmonary but not systemic infection with a high-virulence strain of C. neoformans significantly induced pulmonary IL-25 expression in the lungs but not brains. In response to pulmonary infection, mice deficient in the surface IL-17 receptor B, a component of the IL-25R, exhibited improved survival with a decreased brain fungal burden. The absence of IL-25R signaling diminished the type 2 and enhanced the type 1 immune response that directed macrophage polarization toward M1 macrophages. Interestingly, Cryptococcus -mediated IL-25 signaling suppressed the expression of cytokines and chemokines associated with protection in the brain, including Ifng, Il1b, Ip10, and Nos2 , without affecting brain cellular inflammation and microglia cell activation. Il17rb -/- mice receiving cryptococcal-specific CD4 + T cells from wild-type had a shorter survival time with higher fungal burden within the brain and an elevated expression of M2 macrophage markers than those receiving cryptococcal-specific CD4 + T cells from Il17rb -/- mice. Taken together, our data indicated that IL-25 signaling subverts the induction of protective immunity and amplifies the type 2 immune response that may favor the development of cryptococcal disease and the fungal dissemination to the CNS., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Hematopoietic stem cell (HSC) aging correlates with an increasing risk of myeloproliferative disease and immunosenescence. In this study, we show that aging-related inflammation promotes HSC aging through tumor necrosis factor-α (TNF-α)→ERK→ETS1→interleukin27Ra (IL27Ra) pathway. TNF-α, a well-known biomarker of inflammation, increases during aging and induces the expression of IL27Ra on HSCs via ERK-ETS1 signaling. Deletion of IL27Ra rescues the functional decline and myeloid bias of HSCs and also reverses the inhibitory effect of TNF-α on HSCs. Aged IL27Ra-/- mice had a reduced proportion of myeloid-biased HSCs and did not display the biased myeloid differentiation that occurs in aged wild-type mice. IL27Ra+ HSCs exhibit impaired reconstitution capacity and myeloid-bias compared with IL27Ra- HSCs and serve as a myeloid-recovery pool upon inflammatory insult. Inflammation-related genes were enriched in IL27Ra+ HSCs and this enrichment increases with aging. Our study demonstrates that age-induced IL27Ra signaling impairs HSCs and raises the possibility that interfering with IL27Ra signaling can counter the physiologically deleterious effect of aging on hematopoietic capacity., (© 2020 by The American Society of Hematology.)

The footprint of cytokines is evident in almost every biological process, such as development, as well as the pathogenesis of the different diseases, immune responses to pathogens, etc. These small proteins are categorized into different functional classes; for instance, they can play a pro-inflammatory or anti-inflammatory role in different situations, or they can confer a polarization to the immune system. Interleukin (IL)-27 is a member of the IL-12 family. Antigen-presenting cells are the primary source of IL-27 production, which exerts its effects by bindings to the IL-27 receptor expressed on the surface of target cells. Interaction of IL-27 and IL-27 receptor leads to activation of the JAK-STAT and p38 MAPK signaling pathways. Most studies focused on the inflammatory effects of this cytokine, but gradually anti-inflammatory effects were also revealed for this cytokine, which changed the traditional perception of the function of this cytokine. The functionality of IL-27 in the pathogenesis of rheumatic diseases has been attributed to a double-blade sword. Hence, novel therapeutic approaches have been devised targeting IL-12 family that has been accompanied with promising results. In this review, we focused on the inflammatory and anti-inflammatory properties of IL-27 in different autoimmune rheumatologic diseases and its plausible therapeutic potentials., Competing Interests: 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 © 2020 Elsevier B.V. All rights reserved.)

Recently, the era of medicine has been encountered with the exponential growth of special seroimmunobiomarkers in clinical trials. Lately, Interleukin-37 (IL-37) has attracted a wide range of basic medical scientists' attention due to its controversial functions in physiologic or pathologic microenvironments. In this research, an updated overview of immunobiological functions and clinical applications of IL-37 in a wide range of diseases, are discussed in order to highlight the role of recent laboratory-based results of IL-37. Data of this systematic review article were collected from initial 237 articles in Google Scholar search engine, Science Direct, PubMed, Scopus, and Embase databases. Eventually, 134 total articles were considered from March 2000 to June 2019 time interval, by using 5 keywords. Relevant English articles, abstracts and conference papers all were included. No restrictions of methods and type of the article were imposed. As one of the newly immunotherapeutic based approaches, clinical applications of cytokines are promisingly taken into account for diagnosis and treatment of multiple diseases. Various evidence suggests that IL-37 has notable roles in the regulation of acute and chronic inflammatory responses. Also, IL-37 has been studied in pregnancy, obesity, infectious, cardiovascular, neurologic, autoimmune, and metabolic diseases. Also, the protective functions of IL-37 against multiple cancers, are disputably related to the type and stage of cancer as well as the IL-37 variant. The broad spectrum of IL-37 and its receptors in diseases, seem to be a potential candidate with pivotal effects for immunomodulation and immune gene therapy of various pathologic states.

Candida albicans, a ubiquitous commensal fungus that colonizes human mucosal tissues and skin, can become pathogenic, clinically manifesting most commonly as oropharyngeal candidiasis and vulvovaginal candidiasis (VVC). Studies in mice and humans convincingly show that T-helper 17 (Th17)/interleukin 17 (IL-17)-driven immunity is essential to control oral and dermal candidiasis. However, the role of the IL-17 pathway during VVC remains controversial, with conflicting reports from human data and mouse models. Like others, we observed induction of a strong IL-17-related gene signature in the vagina during estrogen-dependent murine VVC. As estrogen increases susceptibility to vaginal colonization and resulting immunopathology, we asked whether estrogen use in the standard VVC model masks a role for the Th17/IL-17 axis. We demonstrate that mice lacking IL-17RA, Act1, or interleukin 22 showed no evidence for altered VVC susceptibility or immunopathology, regardless of estrogen administration. Hence, these data support the emerging consensus that Th17/IL-17 axis signaling is dispensable for the immunopathogenesis of VVC., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Recent advances in our understanding of the immunopathogenesis of psoriasis have resulted in novel therapeutic agents. IL-23, mainly produced by dendritic cells, maintains the differentiation of naive T cells to Th17 cells, the keystone effector cells in psoriasis. The clinical effectiveness of therapeutic agents targeting this cytokine has been demonstrated in moderate-to-severe plaque psoriasis. Guselkumab is the first human antibody against the p40 subunit of the IL-23 receptor approved by the US FDA and the EMA for this indication in adult patients (2017). It has also been approved for treatment of psoriatic arthritis in Japan (April 2018). This article reviews the published data relating to the efficacy and safety of guselkumab for treatment of moderate-to-severe plaque psoriasis.

Adenoviral vectors are being developed as vaccines against infectious agents and tumour-associated antigens, because of their ability to induce cellular immunity. However, the protection afforded in animal models has not easily translated into primates and clinical trials, underlying the need for improving adenoviral vaccines-induced immunogenicity. A Toll-like receptor signalling molecule, TRAM, was assessed for its ability to modify the immune responses induced by an adenovirus-based vaccine. Different adenovirus vectors either expressing TRAM alone or co-expressing TRAM along with a model antigen were constructed. The modification of T-cell and antibody responses induced by TRAM was assessed in vivo in mice and in primates. Co-expression of TRAM and an antigen from adenoviruses increased the transgene-specific CD8+ T cell responses in mice. Similar effects were seen when a TRAM expressing virus was co-administered with the antigen-expressing adenovirus. However, in primate studies, co-administration of a TRAM expressing adenovirus with a vaccine expressing the ME-TRAP malaria antigen had no significant effect on the immune responses. While these results support the idea that modification of innate immune signalling by genetic vectors modifies immunogenicity, they also emphasise the difficulty in generalising results from rodents into primates, where the regulatory pathway may be different to that in mice.

IL-23 plays an important role in the development of arthritis and the IL-23 receptor (IL-23R) is expressed on different types of T cells. However, it is not fully clear which IL-23R + T cells are critical in driving T cell-mediated synovitis. We demonstrate, using knock-in IL-23R-GFP reporter (IL-23R GFP/+ ) mice, that CD4 + CCR6 + T cells and γδ T cells, but not CD8 + T cells, express the IL-23R(GFP). During early arthritis, IL-23R(GFP) + CD4 + CCR6 + T cells, but not IL-23R(GFP) + γδ T cells, were present in the inflamed joints. IL-23R GFP/+ mice were bred as homozygotes to obtain IL-23R GFP/GFP (IL-23R deficient/IL-23R -/- ) mice, which express GFP under the IL-23R promotor. Arthritis progression and joint damage were significantly milder in IL-23R -/- mice, which revealed less IL-17A + cells in their lymphoid tissues. Surprisingly, IL-23R -/- mice had increased numbers of IL-23R(GFP) + CD4 + CCR6 + and CCR7 + CD4 + CCR6 + T cells in their spleen compared to WT, and IL-23 suppressed CCR7 expression in vitro. However, IL-23R(GFP) + CD4 + CCR6 + T cells were present in the synovium of IL-23R -/- mice at day 4. Finally, adoptive transfer experiments revealed that CD4 + CCR6 + T cells and not γδ T cells drive arthritis progression. These data suggest that IL-23R-dependent T cell-mediated synovitis is dependent on CD4 + CCR6 + T cells and not on γδ T cells., (© 2019 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: The interleukin (IL)23 pathway contributes to IBD pathogenesis and is being actively studied as a therapeutic target in patients with IBD. Unexpected outcomes in these therapeutic trials have highlighted the importance of understanding the cell types and mechanisms through which IL23 regulates immune outcomes. How IL23 regulates macrophage outcomes and the consequences of the IL23R R381Q IBD-protective variant on macrophages are not well defined; macrophages are key players in IBD pathogenesis and inflammation., Design: We analysed protein and RNA expression, signalling and localisation in human monocyte-derived macrophages (MDMs) through western blot, ELISA, real-time PCR, flow cytometry, immunoprecipitation and microscopy., Results: IL23R was critical for optimal levels of pattern-recognition receptor (PRR)-induced signalling and cytokines in human MDMs. In contrast to the coreceptor IL12Rβ1, IL23 induced dynamic IL23R cell surface regulation and this required clathrin and dynamin-mediated endocytosis and endocytic recycling-dependent pathways; these pathways were essential for IL23R-mediated outcomes. The IBD-protective IL23R R381Q variant showed distinct outcomes. Relative to IL23R R381, HeLa cells expressing IL23R Q381 showed decreased IL23R recycling and reduced assembly of IL23R Q381 with Janus kinase/signal transducer and activator of transcription pathway members. In MDMs from IL23R Q381 carriers, IL23R accumulated in late endosomes and lysosomes on IL23 treatment and cells demonstrated decreased IL23R- and PRR-induced signalling and cytokines relative to IL23R R381 MDMs., Conclusion: Macrophage-mediated inflammatory pathways are key contributors to IBD pathogenesis, and we identify an autocrine/paracrine IL23 requirement in PRR-initiated human macrophage outcomes and in human intestinal myeloid cells, establish that IL23R undergoes ligand-induced recycling, define mechanisms regulating IL23R-induced signalling and determine how the IBD-protective IL23R R381Q variant modulates these processes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Interleukin (IL)-22 is a cytokine involved in tissue protection and repair following lung pathologies. Interferon (IFN)-λ cytokines displayed similar properties during viral infection and a synergy of action between these two players has been documented in the intestine. We hypothesize that during Pseudomonas aeruginosa challenge, IL-22 up-regulates IFN-λ and that IFN-λ exhibits protective functions during Pseudomonas aeruginosa acute pneumonia model in mice., Methods: Using an in vitro human alveolar epithelial cell line A549, we assessed the ability of IL-22 to enhance IFN-λ expression during infection. IFN-λ protective function was evaluated in an acute mouse pneumonia model., Results: We first demonstrated in murine lungs that only type-II alveolar cells express IL-22 receptor and that IL-22 treatment of A549 cell line up-regulates IFN-λ expression. In a murine acute pneumonia model, IL-22 administration maintained significant IFN-λ levels in the broncho-alveolar fluids whereas IL-22 neutralization abolished IFN-λ up-regulation. In vivo administration of IFN-λ during Pseudomonas aeruginosa pneumonia improves mice outcome by dampening neutrophil recruitment and decreasing epithelium damages., Discussion: We show here that IL-22 regulates IFN-λ levels during Pseudomonas aeruginosa pneumonia., (Copyright © 2019. Published by Elsevier Ltd.)

In the epididymis, prevention of autoimmune responses against spermatozoa and simultaneous protection against pathogens is important for male fertility. We have previously shown that mononuclear phagocytes (MPs) are located either in the epididymal interstitium or in close proximity to the epithelium. In the initial segments (IS), these 'intraepithelial' MPs extend slender luminal-reaching projections between epithelial cells. In this study, we performed an in-depth characterisation of MPs isolated from IS, caput-corpus and cauda epididymis of CX3CR1EGFP+/- mice that express EGFP in these cells. Flow cytometry analysis revealed region-specific subsets of MPs that express combinations of markers traditionally described in 'dendritic cells' or 'macrophages'. RNA sequencing identified distinct transcriptomic signatures in MPs from each region and revealed specific genes involved in inflammatory and anti-inflammatory responses, phagosomal activity and antigen processing and presentation. Functional fluorescent in vivo labelling assays showed that higher percentages of CX3CR1+ MPs that captured and processed antigens were detected in the IS compared to other regions. Confocal microscopy showed that in the IS, caput and corpus, circulatory antigens were internalised and processed by interstitial and intraepithelial MPs. However, in the cauda only interstitial MPs internalised and processed antigens, while intraepithelial MPs did not take up antigens, indicating that all antigens have been captured before they reached the epithelial lining. Cauda MPs may thus confer a stronger protection against blood-borne pathogens compared to proximal regions. By identifying immunoregulatory mechanisms in the epididymis, our study may lead to new therapies for male infertility and epididymitis and identify potential targets for immunocontraception., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background & Aims: Interleukin (IL)23 is a major contributor to inflammatory bowel disease (IBD) pathogenesis and is being pursued as a therapeutic target, both through targeting IL23 alone or in combination with IL12. Unexpected trial outcomes highlight the importance of understanding the cell types through which IL23 regulates immune responses, and how IL23 and IL12 compare in these responses. Macrophages are key players in IBD, and IL23 recently was found to promote inflammatory outcomes in human macrophages. This raises the possibility that IL23 may be required for additional essential macrophage functions, in particular microbial clearance, such that either blocking the IL23 pathway or the IL23R-R381Q IBD-protective variant may reduce macrophage-mediated microbial clearance., Methods: We analyzed protein expression, signaling, bacterial uptake, and intracellular bacterial clearance in human monocyte-derived macrophages through Western blot, flow cytometry, and gentamicin protection., Results: Autocrine/paracrine IL23 was critical for optimal levels of pattern-recognition-receptor (PRR)-induced intracellular bacterial clearance in human macrophages. Mechanisms regulated by IL23 included induction of pyruvate dehydrogenase kinase 1-dependent bacterial uptake, and up-regulation of reactive oxygen species through nicotinamide adenine dinucleotide phosphate oxidase members, nitric oxide synthase 2, and autophagy through ATG5 and ATG16L1. Complementing these pathways in IL23R-deficient macrophages restored PRR-induced bacterial uptake and clearance. Janus kinase 2, TYK2, and STAT3 were required for IL23-induced mechanisms. IL23 and IL12 induced antimicrobial pathways to similar levels in human macrophages. Relative to IL23R-R381, transfected IL23R-Q381, or monocyte-derived macrophages from IL23R-Q381 carriers showed reduced bacterial uptake and clearance., Conclusions: We identify that autocrine/paracrine IL23 is required for optimal PRR-enhanced macrophage bacterial uptake and intracellular bacterial clearance, define mechanisms regulating IL23R-induced bacterial clearance, and determine how the IBD-protective IL23R-R381Q variant modulates these processes., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Peritoneal adhesion occurs frequently after gastrointestinal/gynecological surgery. Tissue repair and regeneration are very important during this process. IL-22 is an important cytokine that is secreted from immune cells but functions on mesenchymal cells, such as mesothelial cells. The objective of this study was to investigate the roles of IL-22 and its regulators during adhesion formation. Postsurgical peritoneal drainage fluid from patients and rodent models was examined by enzyme-linked immunosorbent assay and fluorescence-activated cell sorting. It was observed that IL-22 expression in the abdominal cavity was rapidly induced 12 hours after surgery and then slowly decreased to a lower, steady level for up to 7 days after surgery. However, neutralizing IL-22 at the time point at which the highest level of expression was observed failed to reduce adhesion, but neutralizing IL-22 at a later time point, i.e., 3 days after surgery, prevented adhesion significantly. The IL-22 receptor was induced on the mesothelial membrane, and IL-22BP, an inhibitor of IL-22, was reduced 3 days after surgery. Furthermore, IFN-γ was identified to have the ability to induce IL-22R, and IL-18, which was induced by the infiltrating macrophages, was found to inhibit IL-22BP expression both in vivo and in vitro. Together, these data suggest that IL-22 may promote adhesion formation and that the regulation of IL-22, IL-22R, and IL-22BP may have therapeutic potential to prevent adhesion formation after surgery without disturbing the normal immune process., (© 2019 by the Wound Healing Society.)

The decision to pursue a monoclonal antibody (mAb) as a therapeutic for disease intervention requires the assessment of many factors, such as target-biology, including the total target burden and its accessibility at the intended site of action, as well as mAb-specific properties like binding affinity and the pharmacokinetics in serum and tissue. Interleukin-36 receptor (IL-36 R) is a member of the IL-1 family cytokine receptors and an attractive target to treat numerous epithelial-mediated inflammatory conditions, including psoriatic and rheumatoid arthritis, asthma, and chronic obstructive pulmonary disease. However, information concerning the expression profile of IL-36 R at the protein level is minimal, so the feasibility of developing a therapeutic mAb against this target is uncertain. Here, we present a characterization of the properties associated with absorption, distribution, metabolism, and excretion of a high-affinity IL-36 R-targeted surrogate rat (IgG2a) mAb antagonist in preclinical mouse models. The presence of IL-36 R in the periphery was confirmed unequivocally as the driver of non-linear pharmacokinetics in blood/serum, although a predominant site of tissue accumulation was not observed based upon the kinetics of radiotracer. Additionally, the contribution of IL-36 R-mediated catabolism of mAb in kidney was tested in a 5/6 nephrectomized mouse model where minimal effects on serum pharmacokinetics were observed, although analysis of functional mAb in urine suggests that target can influence the amount of mAb excreted. Our data highlight an interesting case of target-mediated drug disposition (TMDD) where low, yet broadly expressed levels of membrane-bound target result in a cumulative effect to drive TMDD behavior typical of a large, saturable target sink. The potential differences between our mouse model and IL-36 R target profile in humans are also presented.

Nonallergic eosinophilic asthma (NAEA) is a clinically distinct subtype of asthma. Thus far, the pathophysiologic mechanisms underlying NAEA have not been fully elucidated. This study aimed to determine the role of IL-23 in the pathogenesis of NAEA. We developed a murine model of NAEA using recombinant IL-23 (rIL-23) plus a nonspecific airway irritant [polyinosinic-polycytidylic acid (polyI:C) or diesel exhaust particles (DEPs)] and investigated whether IL-23 plays an important role in the development of NAEA. Intranasal administration of rIL-23 (0.1 μg/mouse) plus polyI:C (0.01 μg/mouse) or DEPs (10 μg/mouse) without allergen resulted in methacholine bronchial hyperresponsiveness and eosinophilic airway inflammation in mice, which are characteristic features of NAEA. rIL-23 plus a low dose nonspecific airway irritants induced the release of innate cytokines from airway epithelium, including IL-33, thymic stromal lymphopoietin and IL-1β; these factors activated types 2 and 3 innate lymphoid cells (ILC2s and ILC3s). ILC2s and ILC3s, but not CD4+ T cells (i.e., adaptive immune cells), were important in the development of NAEA. In addition, we observed that IL-23 receptor expressions increased in airway epithelial cells, which suggests the existence of a positive autocrine loop in our murine model of NAEA. To our knowledge, this is the first report in which administration of rIL-23 plus a nonspecific airway irritant (polyI:C or DEPs) without allergen resulted in features of NAEA in mice similar to those found in humans. IL-23 may constitute a therapeutic target for NAEA in humans.