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Researchers from Banaras Hindu University in Varanasi, India have conducted a study on the pathogenesis of psoriasis, a chronic skin disease. They focused on the role of the proinflammatory cytokine IL-36 and its impact on the hyperproliferation of keratinocytes, which is a characteristic of psoriasis. Through a mathematical model and global sensitivity analysis, they found that an increase in IL-36 levels could lead to the development of psoriasis. The researchers also proposed that a switch-like increase in the keratinocyte population could be a potential treatment strategy. [Extracted from the article]

The IL-36 cytokines are a recently described subset of the IL-1 family of cytokines, shown to play a role in the pathogenesis of intestinal diseases such as Inflammatory Bowel Disease (IBD). Given the link between IBD and colitis –associated cancer, as well as the involvement of other IL-1 family members in intestinal tumorigenesis, the aim of this work was to investigate whether IL-36 cytokines play a role in the pathogenesis of colon cancer. Whilst research to date has focused on the role of IL-36 family members in augmenting the immune response to induce tumour rejection, very little remains known about IL-36R signalling in tumour cells in this context. In this study we demonstrate that expression of IL-36 family member mRNA and protein are significantly increased in colorectal cancer tissue compared to adjacent non-tumour. In vitro assays showed stimulation of colon cancer cell lines with IL-36R agonists resulted in the activation of the pro-tumorigenic phenotypes of increased cellular migration, invasion and proliferation in both 2D and 3D models. In addition, the IL-36 cytokines induced strong expression of pro-inflammatory chemokines in both human and murine cell lines. Intraperitoneal injection of IL-36Ra significantly reduced tumour burden using the subcutaneous CT26 tumour model in syngeneic Balb/mice, and this was associated with a decrease in Ki-67 expression by tumour cells in the IL-36Ra- treated group relative to untreated, suggesting the inhibition of the pro-proliferative signalling of IL-36 agonists resulted in the decreased tumour size. Moreover, colon cancer cells lacking the IL-36R also showed reduced tumour growth and reduced Ki-67 expression in vivo. Taken together, this data suggests that targeting IL-36R signalling may be a useful targeted therapy for colorectal cancer patients with IL-36R+tumour cells.

IL-36 cytokines are emerging as potent orchestrators of intestinal inflammation and are being implicated in the pathogenesis of inflammatory bowel diseases (IBD). However, the mechanisms through which these cytokines mediate these effects remain to be fully uncovered. Here, we report specifically elevated expression of IL-36α, and not IL-36β or IL-36γ in the serum of newly diagnosed, treatment naïve, paediatric IBD patients and identify T cells as primary cellular mediators of IL-36 responses in the inflamed gut. IL-36R expression on CD4+T cells was found to promote intestinal pathology in a murine model of colitis. Consistent with these effects, IL-36R can act as a potent instructor of CD4+T cell differentiation in vivo, enhancing Th1 responses, while inhibiting the generation of Tregs. In addition, loss of IL-36 responsiveness significantly reduced the migration of pathogenic CD4+T cells towards intestinal tissues and IL-36 was found to act, uniquely among IL-1 family members, to induce the expression of gut homing receptors in proinflammatory murine and human CD4+T cells. These data reveal an important role for IL-36 cytokines in driving the colitogenic potential of CD4+T cells and identify a new mechanism through which they may contribute to disease pathogenesis.

IL-36 cytokines are emerging as potent orchestrators of intestinal inflammation and are being implicated in the pathogenesis of inflammatory bowel diseases (IBD). However, the mechanisms through which these cytokines mediate these effects remain to be fully uncovered. Here, we report specifically elevated expression of IL-36α, and not IL-36β or IL-36γ in the serum of newly diagnosed, treatment naïve, paediatric IBD patients and identify T cells as primary cellular mediators of IL-36 responses in the inflamed gut. IL-36R expression on CD4+T cells was found to promote intestinal pathology in a murine model of colitis. Consistent with these effects, IL-36R can act as a potent instructor of CD4+T cell differentiation in vivo, enhancing Th1 responses, while inhibiting the generation of Tregs. In addition, loss of IL-36 responsiveness significantly reduced the migration of pathogenic CD4+T cells towards intestinal tissues and IL-36 was found to act, uniquely among IL-1 family members, to induce the expression of gut homing receptors in proinflammatory murine and human CD4+T cells. These data reveal an important role for IL-36 cytokines in driving the colitogenic potential of CD4+T cells and identify a new mechanism through which they may contribute to disease pathogenesis.

A patent application titled "Il-36 Secreting Immunoresponsive Cells And Uses Thereof" has been published by the USPTO. The application discusses the development of immunoresponsive cells that express an antigen-recognizing receptor and secrete interleukin 36 (IL-36) polypeptides. These cells have the potential to enhance immune responses, treat neoplasms (including cancer), and increase cytokine production. The application also describes methods for using these cells in therapies to reduce tumor burden, prevent neoplasms, lengthen survival, and enhance immune responses. The method involves introducing nucleic acid sequences encoding an antigen-recognizing receptor and an IL-36 polypeptide into immunoresponsive cells. The cells can be autologous to the recipient, and the method can be used with various types of cells. The application also mentions a kit that includes the immunoresponsive cells, a pharmaceutical composition, the nucleic acid composition, or the vector, along with written instructions. [Extracted from the article]

A recent study conducted by researchers at Zhejiang University School of Medicine has shed light on the role of IL-36 in regulating neutrophil chemotaxis and bone loss in periodontitis. The study found that IL-36g, an agonist of IL-36R, promotes neutrophil chemotaxis through fibroblasts. The researchers also discovered that IL-36g levels increase during periodontitis and that inhibiting IL-36Ra can reduce neutrophil infiltration and bone resorption. These findings provide new insights into the pathophysiology of periodontitis and suggest potential avenues for targeted intervention. [Extracted from the article]

Chimeric antigen receptor (CAR) T-cell therapy has shown remarkable responses in B-cell malignancies. However, many patients suffer from limited response and tumor relapse due to lack of persisting CAR T cells and immune escape. These clinical challenges have compromised the long-term efficacy of CAR T-cell therapy and call for the development of novel CAR designs. We demonstrated that CAR T cells secreting a cytokine interleukin-36? (IL-36?) showed significantly improved CAR T-cell expansion and persistence, and resulted in superior tumor eradication compared with conventional CAR T cells. The enhanced cellular function by IL-36? was mediated through an autocrine manner. In addition, activation of endogenous antigen-presenting cells (APCs) and T cells by IL-36? aided the formation of a secondary antitumor response, which delayed the progression of antigen-negative tumor challenge. Together, our data provide preclinical evidence to support the translation of this design for an improved CAR T-cell-mediated antitumor response.

Objective: This article reviews clinical trial data that assesses the safety, efficacy, and clinical application of spesolimab, an interleukin-36 (IL-36) blocker, for the treatment of generalized pustular psoriasis (GPP).Data sources: A review of the literature was conducted using the search terms: “spesolimab,” “BI 655130,” and “spevigo” in MEDLINE (PubMed) and Clinicaltrials.gov from January 1, 1950 to October 31, 2023.Study selection and data extraction: Relevant articles in English relating to the pharmacodynamics, pharmacokinetics, efficacy, and safety of spesolimab were included.Data Synthesis: In one phase 2 clinical trial evaluating single dose IV spesolimab for GPP flares at day 8, 54% of patients receiving spesolimab had a GPP physician global assessment (GPPGA) pustulation subscore of 0, and 43% had a GPPGA total score of 0 compared with 6% and 11% for the placebo group, respectively. Another phase 2 clinical trial assessing subcutaneous spesolimab found 23% of patients in low-dose, 29% in medium-dose, and 10% of high-dose spesolimab had flares by week 48 compared with 52% of the placebo group. Hazard ratios for time to GPP flare compared with placebo were 0.16 (P= 0.0005), 0.35 (P= 0.0057), and 0.47 (P= 0.027) for the spesolimab groups, respectively. Infection rates were similar across treatment and placebo groups, and severe adverse events such as drug reactions with eosinophilia and systemic symptom (DRESS), cholelithiasis, and breast cancer occurred with spesolimab.Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs: Spesolimab is a first-in-class IL-36 monoclonal antibody receptor antagonist approved for the treatment of acute GPP flares. It is a safe and effective therapeutic agent in preventing future GPP flares, with no current comparator trials with other GPP agents.Conclusion: Spesolimab is a safe and effective treatment for acute GPP flares in adults. Future clinical trials can establish safety and efficacy compared with other agents.

A recent study conducted by researchers from the University Medical Center of the Johannes Gutenberg-University in Mainz, Germany, has found that plaque psoriasis, an autoimmune skin disease, affects 1-3% of the global population. The study focused on the role of IL-36 signaling in psoriasis and found that inhibiting the IL-36 signaling pathway could be a potential treatment for IL-17A-driven psoriasis and its associated comorbidities. The researchers discovered that antibody-mediated inhibition of IL36R suppressed skin inflammation and attenuated psoriasis-associated systemic inflammation. This research provides valuable insights into potential alternative approaches for treating psoriasis. [Extracted from the article]

Netherton syndrome is a rare autosomal recessive skin disease caused by loss-of-function mutations in SPINK5encoding LEKTI protein that results in unopposed activity of epidermal kallikrein-related peptidases (KLKs), mainly KLK5, KLK7, and KLK14. Although the function of KLK5 and KLK7 has been previously studied, the role of KLK14 in skin homeostasis and its contribution to Netherton syndrome pathogenesis remains unknown. We generated a transgenic murine model overexpressing human KLK14(TghKLK14) in stratum granulosum. TghKLK14mice revealed increased proteolytic activity in the granular layers and in hair follicles. Their hair did not grow and displayed major defects with hyperplastic hair follicles when hKLK14 was overexpressed. TghKLK14mice displayed abnormal epidermal hyperproliferation and differentiation. Ultrastructural analysis revealed cell separation in the hair cortex and increased thickness of Huxley’s layer. Desmoglein (Dsg) 2 staining was increased, whereas Dsg3 and Dsg4 were markedly reduced. In vitro studies showed that hKLK14 directly cleaves recombinant human DSG3 and recombinant human DSG4, suggesting that their degradation contributes to hair abnormalities. Their skin showed an inflammatory signature, with enhanced expression of IL-36 family members and their downstream targets involved in innate immunity. This in vivo study identifies KLK14 as an important contributor to hair abnormalities and skin inflammation seen in Netherton syndrome.

Researchers from the First Affiliated Hospital of Xi'an Jiaotong University in China conducted a study to explore whether serum interleukin (IL)-36 subfamily could serve as biomarkers for disease progression in lupus nephritis (LN). They selected 103 patients with systemic lupus erythematosus (SLE) as research subjects and divided them into LN and non-LN groups. The study found that serum levels of IL-36a and IL-17 were elevated in both groups compared to healthy controls, with a more significant increase in the LN group. The researchers concluded that IL-36a may be a biomarker associated with SLE proteinuria and its mechanism of action may be related to the regulation of Th17 cytokines. [Extracted from the article]

Acute generalized exanthematous pustulosis (AGEP) is a severe adverse cutaneous drug reaction. Although an involvement of drug-specific T cells has been reported, the physiopathology of AGEP and mechanism of neutrophilic skin inflammation remain incompletely understood. Recently, mutations in IL-36RN, the gene encoding the IL-36 receptor antagonist, have been reported to be more frequent in AGEP patients and pustular psoriasis. Here, we show that IL-36 cytokines, in particular IL-36γ, are highly expressed in lesional skin of AGEP patients, keratinocytes and macrophages being a major source of IL-36γ. Such an IL-36γ overexpression was not observed in patients with drug-induced maculopapular rash. In vitro, the causative drug specifically induced IL-36γ release either directly by the patient’s peripheral blood monocytes or indirectly by keratinocytes in the presence of autologous peripheral blood mononuclear cells. Such culprit drug induction of IL-36γ secretion in vitro was specific for AGEP and involved toll-like receptor 4 sensing the drug/albumin complex as a danger signal. Our results suggest that IL-36γ secretion by monocytes/macrophages and keratinocytes in response to culprit drug exposure likely plays a key role in the pathogenesis of AGEP.

Keywords: Cytokines; Dermatology; Drugs and Therapies; Health and Medicine; Intercellular Signaling Peptides and Proteins; Papulosquamous Skin Diseases and Conditions; Psoriasis; Skin Diseases and Conditions; Skin and Connective Tissue Diseases and Conditions EN Cytokines Dermatology Drugs and Therapies Health and Medicine Intercellular Signaling Peptides and Proteins Papulosquamous Skin Diseases and Conditions Psoriasis Skin Diseases and Conditions Skin and Connective Tissue Diseases and Conditions 1131 1131 1 10/03/23 20231006 NES 231006 2023 OCT 6 (NewsRx) -- By a News Reporter-Staff News Editor at Drug Week -- Fresh data on psoriasis are presented in a new report. A narrative review was written to further study preclinical and clinical evidence for the role of IL-36 in psoriasis, atopic dermatitis (AD), hidradenitis suppurativa (HS), acne, autoimmune blistering diseases, and neutrophilic dermatoses. Cytokines, Dermatology, Drugs and Therapies, Health and Medicine, Intercellular Signaling Peptides and Proteins, Papulosquamous Skin Diseases and Conditions, Psoriasis, Skin Diseases and Conditions, Skin and Connective Tissue Diseases and Conditions. [Extracted from the article]

Generalized pustular psoriasis (GPP) is the most severe psoriasis variant. Mutations in the IL-36 antagonist IL36RN, in CARD14or AP1S3provide genetic evidence for autoinflammatory etiology but cannot explain its pathogenesis completely. Here we demonstrate that unopposed IL-36 signaling promotes antigen-driven and likely pathogenic T-helper type 17 (Th17) responses in GPP. We observed that CD4+T cells in blood and skin lesions of GPP patients were characterized by intense hyperproliferation, production of the GPP key mediator, IL-17A, and highly restricted TCR repertoires with identical T-cell clones in blood and skin lesions, indicating antigen-driven T-cell expansions. The clonally expanded CD4+T cells were major producers of IL-17A. IL-36 signaling substantially enhanced TCR-mediated proliferation of CD4+T cells. Moreover, GPP patients showed preferences for HLA-DRB1∗14, HLA-DQB1∗05, and HLA-DQB1∗03. We conclude that in GPP unopposed IL-36 signaling and certain HLA-class II alleles may cooperate in promoting antigen-driven Th17 responses, which in the obvious absence of exogenous triggers may reflect autoimmune reactions. This study reveals a pathogenic pathway where innate immune dysregulation promotes T-cell−mediated inflammation in GPP.

Keywords: Shanghai; People's Republic of China; Asia; Cancer; Connective Tissue Cells; Health and Medicine; Immunology; Macrophages; Melanoma; Mononuclear Phagocyte System; Myeloid Cells; Oncology; Phagocytes EN Shanghai People's Republic of China Asia Cancer Connective Tissue Cells Health and Medicine Immunology Macrophages Melanoma Mononuclear Phagocyte System Myeloid Cells Oncology Phagocytes 1709 1709 1 07/24/23 20230725 NES 230725 2023 JUL 28 (NewsRx) -- By a News Reporter-Staff News Editor at Immunotherapy Weekly -- Investigators discuss new findings in Oncology - Melanoma. People's Republic of China, Asia, Cancer, Connective Tissue Cells, Health and Medicine, Immunology, Macrophages, Melanoma, Mononuclear Phagocyte System, Myeloid Cells, Oncology, Phagocytes, Shanghai Furthermore, IL-36 alpha synergized with the PD-L1 antibody increased the immune cells infiltration and enhanced the anti-tumor effect of the PD-L1 antibody on melanoma.". [Extracted from the article]

0% ulceration apparent and lesion is dry Almost clear; 25% of active ulceration present; more than 90% granulation tissue present with mild pink, slightly elevated borders. Some evidence of granulation tissue with multiple purulent drops and significant purulence on ulcer bed at presentation Severe; 100% active ulcer with violaceous, raised rolled borders. Keywords: Cardio Device; Clinical Research; Clinical Trials and Studies; Contraception; Contraceptives; Drugs and Therapies; Health and Medicine; Hyperpigmentation; Medical Devices; Neurologic Manifestations; Pain; Pigmentation Disorders; Pyoderma; Quality of Life; Reproductive Medicine; Reproductive Techniques; Skin Diseases and Conditions; Skin Diseases and Conditions - Hyperpigmentation; Skin and Connective Tissue Diseases and Conditions; Ulcers EN Cardio Device Clinical Research Clinical Trials and Studies Contraception Contraceptives Drugs and Therapies Health and Medicine Hyperpigmentation Medical Devices Neurologic Manifestations Pain Pigmentation Disorders Pyoderma Quality of Life Reproductive Medicine Reproductive Techniques Skin Diseases and Conditions Skin Diseases and Conditions - Hyperpigmentation Skin and Connective Tissue Diseases and Conditions Ulcers 257 257 1 11/06/23 20231112 NES 231112 2023 NOV 6 (NewsRx) -- By a News Reporter-Staff News Editor at Vaccine Weekly -- Staff editors report on the newly launched clinical trial, NCT06092216, which has the following summary description: "The purpose of this research study is to assess the feasibility of using spesolimab in participants with moderate to severe pyoderma ganrenosum. [Extracted from the article]

Influenza virus causes a respiratory disease in humans that can progress to lung injury with fatal outcome. The interleukin (IL)-36 cytokines are newly described IL-1 family cytokines that promote inflammatory responses via binding to the IL-36 receptor (IL-36R). The mechanism of expression and the role of IL-36 cytokines are poorly understood. Here, we investigated the role of IL-36 cytokines in modulating the innate inflammatory response during influenza virus-induced pneumonia in mice. The intranasal administration of influenza virus upregulated IL-36α mRNA and protein production in the lungs. In vitro, influenza virus-mediated IL-36α but not IL-36γ is induced and secreted from alveolar epithelial cells (AECs) through both a caspase-1 and caspase-3/7 dependent pathway. IL-36α was detected in microparticles shed from AECs and promoted the production of pro-inflammatory cytokines and chemokines in respiratory cells. IL-36R-deficient mice were protected from influenza virus-induced lung injury and mortality. Decreased mortality was associated with significantly reduced early accumulation of neutrophils and monocytes/macrophages, activation of lymphocytes, production of pro-inflammatory cytokines and chemokines, and permeability of the alveolar–epithelial barrier in despite impaired viral clearance. Taken together, these data indicate that IL-36 ligands exacerbate lung injury during influenza virus infection.

Neutrophil granule proteases are thought to function as anti-microbial effectors, cooperatively hydrolyzing microorganisms within phagosomes, or upon deployment into the extracellular space. However, evidence also suggests that neutrophil proteases play an important role in the coordination and escalation of inflammatory reactions, but how this is achieved has been obscure. IL-1 family cytokines are important initiators of inflammation and are typically released via necrosis but require proteolytic processing for activation. Here, we show that proteases liberated from activated neutrophils can positively or negatively regulate the activity of six IL-1 family cytokines (IL-1α, IL-1β, IL-33, IL-36α, IL-36β, and IL-36γ) with exquisite sensitivity. In contrast, extracellular neutrophil proteases displayed very poor bactericidal activity, exhibiting 100-fold greater potency toward cytokine processing than bacterial killing. Thus, in addition to their classical role as phagocytes, neutrophils play an important immunoregulatory role through deployment of their granule proteases into the extracellular space to process multiple IL-1 family cytokines.

Prominent skin involvement is a defining characteristic of autoinflammatory disorders caused by abnormal IL-1 signaling. However, the pathways and cell types that drive cutaneous autoinflammatory features remain poorly understood. We sought to address this issue by investigating the pathogenesis of pustular psoriasis, a model of autoinflammatory disorders with predominant cutaneous manifestations. We specifically characterized the impact of mutations affecting AP1S3, a disease gene previously identified by our group and validated here in a newly ascertained patient resource. We first showed that AP1S3expression is distinctively elevated in keratinocytes. Because AP1S3encodes a protein implicated in autophagosome formation, we next investigated the effects of gene silencing on this pathway. We found that AP1S3knockout disrupts keratinocyte autophagy, causing abnormal accumulation of p62, an adaptor protein mediating NF-κB activation. We showed that as a consequence, AP1S3-deficient cells up-regulate IL-1 signaling and overexpress IL-36α, a cytokine that is emerging as an important mediator of skin inflammation. These abnormal immune profiles were recapitulated by pharmacological inhibition of autophagy and verified in patient keratinocytes, where they were reversed by IL-36 blockade. These findings show that keratinocytes play a key role in skin autoinflammation and identify autophagy modulation of IL-36 signaling as a therapeutic target.

Recent evidence has strongly implicated the IL-1 family cytokines IL-36α, IL-36β, and IL-36γ as key initiators of skin inflammation. Similar to the other members of the IL-1 family, IL-36 cytokines are expressed as inactive precursors and require proteolytic processing for activation; however, the responsible proteases are unknown. Here, we show that IL-36α, IL-36β, and IL-36γ are activated differentially by the neutrophil granule-derived proteases cathepsin G, elastase, and proteinase-3, increasing their biological activity ∼500-fold. Active IL-36 promoted a strong pro-inflammatory signature in primary keratinocytes and was sufficient to perturb skin differentiation in a reconstituted 3D human skin model, producing features resembling psoriasis. Furthermore, skin eluates from psoriasis patients displayed significantly elevated cathepsin G-like activity that was sufficient to activate IL-36β. These data identify neutrophil granule proteases as potent IL-36-activating enzymes, adding to our understanding of how neutrophils escalate inflammatory reactions. Inhibition of neutrophil-derived proteases may therefore have therapeutic benefits in psoriasis.

Keywords: Jiangsu; People's Republic of China; Asia; Cancer; Colon Cancer; Colorectal Research; Gastroenterology; Health and Medicine; Inflammation; Oncology EN Jiangsu People's Republic of China Asia Cancer Colon Cancer Colorectal Research Gastroenterology Health and Medicine Inflammation Oncology 362 362 1 06/12/23 20230613 NES 230613 2023 JUN 13 (NewsRx) -- By a News Reporter-Staff News Editor at Cancer Weekly -- New research on Oncology - Colon Cancer is the subject of a report. Keywords for this news article include: Jiangsu, People's Republic of China, Asia, Cancer, Colon Cancer, Colorectal Research, Gastroenterology, Health and Medicine, Inflammation, Oncology, Nanjing Medical University. [Extracted from the article]

Keywords for this news article include: Zhejiang, People's Republic of China, Asia, Endocrine System Diseases and Conditions, Health and Medicine, Thyroid Diseases and Conditions, Thyroiditis, Thyronines, Triiodothyronine, Ningbo University. Zhejiang, People's Republic of China, Asia, Endocrine System Diseases and Conditions, Health and Medicine, Thyroid Diseases and Conditions, Thyroiditis, Thyronines, Triiodothyronine Thyroid function and measurements of thyroid-stimulating hormone (TSH), free triiodothyronine 3, free triiodothyronine 4 (FT4), thyroid peroxidase antibody (TPO-Ab), and thyroid globulin antibody were measured using a fully automated chemiluminescent immunoassay analyzer. [Extracted from the article]

IL-36 is another family member of IL-1 and induces the production of proinflammatory cytokines and activates MAPK and NF?B pathways. IL-36 is a common mediator of innate and adaptive immune response and is inhibited by IL-36 receptor antagonist (RA). IL-36RA acts on IL-36 receptor ligand which exerts proinflammatory effect in vivoand in vitro. IL-38 binds to IL-36 receptor as does IL-36RA and has similar biological effects on immune cells. IL-38 is also a member of IL-1 cytokine and shares some characteristics of IL-1RA, binding the same IL-1 receptor type I. IL-38 plays a role in the pathogenesis of inflammatory diseases, exerting protective effect in some autoimmune diseases. Both IL-38 and IL-36RA have an anti-inflammatory biological effect, however in some cases have contrary effects.

The interleukin-1 (IL-1) superfamily of cytokines comprises a set of pivotal mediators of inflammation. Among them, the action of IL-36 cytokines in immune responses has remained elusive. In a recent study, we demonstrated a direct effect of IL-36 on immune cells. Here we show that, among T cells, the IL-36 receptor is predominantly expressed on naive CD4+ T cells and that IL-36 cytokines act directly on naive T cells by enhancing both cell proliferation and IL-2 secretion. IL-36β acts in synergy with IL-12 to promote Th1 polarization and IL-36 signaling is also involved in mediating Th1 immune responses to Bacillus Calmette-Guerin infection in vivo. Our findings point toward a critical function of IL-36 in the priming of Th1 cell responses in vitro, and in adaptive immunity in a model of mycobacterial infection in vivo.

The interleukin-1 (IL-1) superfamily of cytokines comprises a set of pivotal mediators of inflammation. Among them, the action of IL-36 cytokines in immune responses has remained elusive. In a recent study, we demonstrated a direct effect of IL-36 on immune cells. Here we show that, among T cells, the IL-36 receptor is predominantly expressed on naive CD4+T cells and that IL-36 cytokines act directly on naive T cells by enhancing both cell proliferation and IL-2 secretion. IL-36β acts in synergy with IL-12 to promote Th1 polarization and IL-36 signaling is also involved in mediating Th1 immune responses to Bacillus Calmette-Guerin infection in vivo. Our findings point toward a critical function of IL-36 in the priming of Th1 cell responses in vitro, and in adaptive immunity in a model of mycobacterial infection in vivo.

Psoriasis is an immune-mediated skin disorder associated with severe systemic comorbidities. Whereas IL-36 is a key disease driver, the pathogenic role of this cytokine has mainly been investigated in skin. Thus, its effects on systemic immunity and extracutaneous disease manifestations remain poorly understood. To address this issue, we investigated the consequences of excessive IL-36 activity in circulating immune cells. We initially focused our attention on generalized pustular psoriasis (GPP), a clinical variant associated with pervasive upregulation of IL-36 signaling. By undertaking blood and neutrophil RNA sequencing, we demonstrated that affected individuals display a prominent IFN-I signature, which correlates with abnormal IL-36 activity. We then validated the association between IL-36 deregulation and IFN-I over-expression in patients with severe psoriasis vulgaris (PV). We also found that the activation of IFN-I genes was associated with extracutaneous morbidity, in both GPP and PV. Finally, we undertook mechanistic experiments, demonstrating that IL-36 acts directly on plasmacytoid dendritic cells, where it potentiates toll-like receptor (TLR)-9 activation and IFN-α production. This effect was mediated by the upregulation of PLSCR1, a phospholipid scramblase mediating endosomal TLR-9 translocation. These findings identify an IL-36/ IFN-I axis contributing to extracutaneous inflammation in psoriasis.

TGFBR2 regulates IL-36 to contribute to joint homeostasis, and an IL-36 receptor antagonist can ameliorate osteoarthritis in mouse models.