Interleukin-36 Cytokines Research Articles

Serum IL-36β levels are associated with Insulin sensitivity in paediatric patients with obesity

Although the orchestrating role of Interleukin-36 cytokines in regulating inflammation at barrier tissue sites, is well established, whether they play a significant role in the settings of metabolic health and disease, has yet to be fully established. Several recent studies have demonstrated that IL-36 cytokine expression is elevated among adult patients with obesity, and can play roles in regulating both insulin sensitivity and driving inflammation. In this report, we have extended these analyses to paediatric patients and identified an association between elevated serum levels of expression of the specific Interleukin-36 subfamily member, IL-36β, among children with obesity displaying insulin sensitivity, compared to children with obesity who are insulin resistant. While these data further indicate a possible protective role for IL-36 in metabolic health, they also differ with previous findings from an adult patient cohort, where elevated levels of the related cytokine, IL-36γ, were found to occur in association with improved metabolic health. While highlighting important differences between paediatric and adult patient cohorts in the context of metabolic disease associated with obesity, these data underscore the need for a deeper mechanistic analysis of the role of IL-36 cytokines in disease.

The diagnostic value of interleukin-36 cytokines in pleural effusions of varying etiologies

BackgroundThe clinical management of pleural effusion (PE) poses challenges due to its diverse etiologies. The objective of this research was to investigate the concentrations of interleukin-36 (IL-36) cytokines in pleural fluid (PF) from different etiologies and assess their diagnostic efficacy in distinguishing the causes of PE. MethodsThis study enrolled 89 patients with confirmed PE, comprising 11 cases classified as transudate, 24 cases as malignant pleural effusion (MPE), 24 cases as tuberculous pleural effusion (TPE), and 30 cases as parapneumonic pleural effusion (PPE). The PPE group was further subdivided into 20 cases of uncomplicated parapneumonic effusion (UPPE) and 10 cases of complicated parapneumonic effusion (CPPE)/empyema. The concentrations of IL-36 cytokines in the PF of all 89 patients were quantified by the enzyme-linked immunosorbent assay (ELISA). ResultsIL-36α exhibited excellent diagnostic accuracy in TPE, achieving a sensitivity of 91.7 % and specificity of 83.1 %, along with a cut-off value of 435.3 pg/ml. IL-36Ra also demonstrated relatively favorable diagnostic performance in PPE, with a sensitivity of 80.0 % and specificity of 76.3 %, along with a cut-off value of 390.8 pg/ml. Multivariable logistic regression models were successfully developed for both TPE and PPE, confirming their diagnostic utility. Furthermore, the levels of IL-36Ra were notably elevated in CPPE/empyema in comparison to UPPE. Moreover, in PF, IL-36γ exhibited positive associations with both IL-36α and IL-36Ra. ConclusionIL-36α and IL-36Ra may serve as novel biomarkers for diagnosing TPE and PPE, respectively. The multivariate models established significantly enhance the diagnostic efficacy of both TPE and PPE. Furthermore, IL-36Ra can function as an indicator for assessing the extent of pleural inflammation. Additionally, the interaction among IL-36 cytokines in PF may contribute to their expression modulation.

Interleukin-36 cytokines are overexpressed in the skin and sera of patients with bullous pemphigoid.

Bullous pemphigoid (BP) is an autoimmune bullous disease, characterized by autoantibodies targeting BP180 and BP230. The role of interleukin (IL)-36, a potent chemoattractant for granulocytes, in BP remains elusive.The expression of IL-36 cytokines (IL-36α, β, γ) and their antagonists (IL-36Ra and IL-38) was analysed in the skin and serum samples of patients with BP (n= 31), psoriasis (n= 10) and healthy controls (HC) (n= 14) by quantitative polymerase chain reaction and enzyme linked immunosorbent assay, respectively. Skin and serum levels of all cytokines were correlated with the Bullous Pemphigoid Disease Area Index (BPDAI) score and with the serum concentration of pathogenic antibodies.IL-36α, IL-36β, IL-36γ and IL-36Ra were significantly (p< 0.05) overexpressed in BP skin compared to HC, without remarkable differences relative to psoriasis skin. The expression of IL-38 was significantly (p< 0.05) higher in BP compared to psoriasis skin.IL-36α and γ, but not β, serum concentrations were significantly (p< 0.05) higher in BP compared to HC. IL-36γ was significantly (p< 0.05) more expressed in the serum of psoriasis patients than BP. The serum concentration of IL-36Ra and IL-38 were similar between BP and HC, while IL-38 serum levels were significantly (p< 0.05) higher in BP compared to psoriasis patients. Serum IL-36α correlated significantly with BPDAI (r= 0.5 p= 0.001).IL-36 agonists are increased in BP patients, both locally and systemically. Serum IL-36α might represent a potential biomarker for BP. An inefficient balance between IL-36 agonists and antagonists is likely to occur during BP inflammation.

Plasma IL-36α and IL-36γ as Potential Biomarkers in Interstitial Lung Disease Associated with Rheumatoid Arthritis: a Pilot Study in the Chinese Population.

Interstitial lung disease (ILD) is a frequent extra-articular manifestation of rheumatoid arthritis (RA) and increases mortality in patients with RA. Early identification of ILD, especially the usual interstitial pneumonia (UIP) pattern with a poor prognosis, is important for guiding treatment of RA-ILD and preventing damage resulting from a delay in diagnosis. Interleukin-36 (IL-36) cytokines are involved in connective tissue diseases. However, IL-36 expression in RA-ILD is unknown. In this study, the clinical relevance of plasma IL-36 cytokines was evaluated in 39 patients with RA-ILD and three other groups (30 healthy controls [HCs], 35 RA patients without ILD, and 27 patients with idiopathic pulmonary fibrosis [IPF]) in the Chinese population. Plasma IL-36α and IL-36γ concentrations were elevated in patients with RA-ILD compared with those in HCs and patients with RA. RA-ILD patients with UIP pattern had higher plasma IL-36γ concentrations than those with RA-ILD without UIP, but these were lower than those in patients with IPF. Receiver operating curve analysis suggested that IL-36α and IL-36γ were potential biomarkers for identifying ILD in patients with RA. Additionally, the optimal cutoff value of IL-36γ for distinguishing RA-ILD with the UIP pattern from RA-ILD without UIP was 555.40pg/mL and that for distinguishing RA-ILD from IPF was 655.10pg/mL. No significant difference in plasma IL-36β or IL-36Ra concentrations was found between patients with RA-ILD and the three other groups. We also found that the lungs originating from different types of patients with PF, including RA-ILD and IPF, and those from mice following bleomycin-induced PF were characterized by increased IL-36γ expression. Our findings suggest that using IL-36 cytokines to identify patients with RA for further ILD workups may provide additional diagnostic value to the current clinically available assays. Moreover, IL-36γ may help to identify the presence of the UIP pattern in patients with RA-ILD and to discriminate RA-ILD from IPF.

Interleukin-36 Cytokines in Infectious and Non-Infectious Lung Diseases.

The IL-36 family of cytokines were identified in the early 2000’s as a new subfamily of the IL-1 cytokine family, and since then, the role of IL-36 cytokines during various inflammatory processes has been characterized. While most of the research has focused on the role of these cytokines in autoimmune skin diseases such as psoriasis and dermatitis, recent studies have also shown the importance of IL-36 cytokines in the lung inflammatory response during infectious and non-infectious diseases. In this review, we discuss the biology of IL-36 cytokines in terms of how they are produced and activated, as well as their effects on myeloid and lymphoid cells during inflammation. We also discuss the role of these cytokines during lung infectious diseases caused by bacteria and influenza virus, as well as other inflammatory conditions in the lungs such as allergic asthma, lung fibrosis, chronic obstructive pulmonary disease, cystic fibrosis and cancer. Finally, we discuss the current therapeutic advances that target the IL-36 pathway and the possibility to extend these tools to treat lung inflammatory diseases.

IL-36 cytokines and gut immunity.

Interleukin 36 (IL-36) constitutes a group of cytokines that belong to the IL-1 superfamily. Emerging evidence has suggested a role of IL-36 in the pathogenesis of many inflammatory disorders. Intriguingly, in the gastrointestinal tract, IL-36 has a rather complex function. IL-36 receptor ligands are overexpressed in both animal colitis models and human IBD patients and may play both pathogenic and protective roles, depending on the context. IL-36 cytokines comprise three receptor agonists: IL-36α, IL-36β and IL-36γ, and two receptor antagonists: IL-36Ra and IL-38. All IL-36 receptor agonists bind to the IL-36R complex and exert pleiotropic effects during inflammatory settings. Here, we first briefly review the processing and secretion of IL-36 cytokines. We then focus on the current understanding of the immunology effects of IL-36 in gut immunity. In addition, we also discuss the ongoing trials that aim to blockage IL-36R signalling for treating chronic intestinal inflammation and present some unexplored questions regarding IL-36 research.

Effect of Interleukin-36β on Activating Autophagy of CD4+CD25+ Regulatory T cells and Its Immune Regulation in Sepsis.

CD4+CD25+ regulatory T cells (Tregs) play an essential role in sepsis-induced immunosuppression. How, the effects of interleukin 36 (IL-36) cytokines on CD4+CD25+ Tregs and their underlying mechanism(s) in sepsis remain unknown. Our study was designed to investigate the impacts of IL-36 cytokines on murine CD4+CD25+ Tregs in presence of lipopolysaccharide (LPS) and in a mouse model of sepsis induced by cecal ligation and puncture (CLP). IL-36-activated autophagy was evaluated by autophagy markers, autophagosome formation, and autophagic flux. IL-36α, IL-36β, and IL-36γ were expressed in murine CD4+CD25+ Tregs. Stimulation of CD4+CD25+ Tregs with LPS markedly up-regulated the expression of these cytokines, particularly IL-36β. IL-36β strongly suppressed CD4+CD25+ Tregs under LPS stimulation and in septic mice challenged with CLP, resulting in the amplification of T-helper 1 response and the proliferation of effector T cells. Mechanistic studies revealed that IL-36β triggered autophagy of CD4+CD25+ Tregs. These effects were significantly attenuated in the presence of the autophagy inhibitor 3-methyladenine or Beclin1 knockdown. In addition, early IL-36β administration reduced the mortality rate in mice subjected to CLP. Depletion of CD4+CD25+ Tregs before the onset of sepsis obviously abrogated IL-36β-mediated protection against sepsis. These findings suggest that IL-36β diminishes the immunosuppressive activity of CD4+CD25+ Tregs by activating the autophagic process, thereby contributing to improvement of the host immune response and prognosis in sepsis.

IL-36α contributes to enhanced T helper 17 type responses in allergic rhinitis

BackgroundT helper 17 (Th17) cell subsets, belongs to CD4+ T cell lineage, are proved to be closely related to pathophysiology of AR recently. The interleukin-36 (IL-36) had been reported to promote the up-regulation of Th17 cytokines in psoriasis. We investigated the regulation of Th17 inflammation by IL-36 family cytokines in allergic rhinitis (AR). MethodsTwenty-one patients with AR and 20 healthy controls were enrolled. The expression of serum protein and mRNA of IL-36 family cytokines between AR and control group were detected and compared. Human peripheral blood mononuclear cells were purified and stimulated by IL-36 cytokines. The transcription factor and production of Th17 cytokines by Th17 cells were evaluated. Mouse model with AR was established to confirm the in vitro results. ResultsThe serum expression of IL-36 cytokines and Th17 cytokines (IL-17 and IL-23) of AR patients were up-regulated significantly compared with controls. The IL-36α promoted the differentiation and function of Th17 cells. The anti-IL-36α treatment could alleviate the Th17 response in AR mice, presented with alleviated symptoms, decreased infiltration of Th17 cells and down-regulated Th17 cytokines expression. ConclusionsIL-36α was involved in the regulation of Th17 responses in allergic rhinitis.

Interleukin-36 cytokines alter the intestinal microbiome and can protect against obesity and metabolic dysfunction

Members of the interleukin-1 (IL-1) family are important mediators of obesity and metabolic disease and have been described to often play opposing roles. Here we report that the interleukin-36 (IL-36) subfamily can play a protective role against the development of disease. Elevated IL-36 cytokine expression is found in the serum of obese patients and negatively correlates with blood glucose levels among those presenting with type 2 diabetes. Mice lacking IL-36Ra, an IL-36 family signalling antagonist, develop less diet-induced weight gain, hyperglycemia and insulin resistance. These protective effects correlate with increased abundance of the metabolically protective bacteria Akkermansia muciniphila in the intestinal microbiome. IL-36 cytokines promote its outgrowth as well as increased colonic mucus secretion. These findings identify a protective role for IL-36 cytokines in obesity and metabolic disease, adding to the current understanding of the role the broader IL-1 family plays in regulating disease pathogenesis.

Interleukin-36 in Infectious and Inflammatory Skin Diseases.

Interleukin-36 (IL-36) comprises to a cytokine family consisting of four isoforms IL-36α, IL-36β, IL-36γ, and IL-36 receptor antagonist (IL-36 Ra). These IL-36 cytokines, in turn, belong to the IL-1 superfamily. The IL-36 receptor (IL-1R6) is functional as a heterodimer formed of IL-1R6 and IL-1 receptor accessory protein (IL-1RAcP). IL-36α, IL-36β, and IL-36γ are regarded as pro-inflammatory ligands and IL-36 Ra as well as IL-38 as anti-inflammatory ligands of IL-1R6. IL-36 cytokines are mainly expressed on the barrier sites of the body e.g., bronchial, intestinal, and dermal epithelium. One of their most important biological functions is the bridging of innate and adaptive immune responses. A disturbed balance between pro-inflammatory and anti-inflammatory branches easily leads to inflammation of the corresponding tissue. The most prominent example for an altered IL-36 expression is the spectrum of psoriasis. In addition to inflammatory dermatoses, IL-36 also seems to play a role in infectious dermatoses. Microbial triggers, especially Staphylococcus aureus infection, increase the production of pro-inflammatory IL-36 cytokines and initiate/promote the inflammation of skin lesions. Due to the discovery of IL-36 as an important immune mediator, it has already been possible to develop important diagnostic tools for dermatitis. Not only in the field of inflammatory skin diseases, but also in pulmonary and intestinal inflammation, there is evidence that IL-36 cytokines might have diagnostic and/or therapeutic relevance.

The role of IL-36γ and its regulation in eosinophilic inflammation in allergic rhinitis

BackgroundAllergic rhinitis (AR) is characterized by eosinophilic inflammation. However, the function and regulation of eosinophils in AR are largely unknown. This study aimed to explore the expression and role of interleukin-36 (IL-36) cytokines in AR. MethodsSixty AR patients and 20 control subjects were recruited in this study. The mRNA and protein expression of serum IL-36 family cytokines and IL-36R in AR were detected by quantitative RT-PCR and enzyme-linked immunosorbent assay ELISA, respectively. IL-36R expression and regulation by eosinophils and the role of IL-36γ in the survival, adhesion, migration and activation of eosinophils were performed in purified eosinophils. Human nasal epithelial cell line was cultured and treated with different stimulators and IL-36γ was measured. ResultsThe mRNA and protein expression of serum IL-36 cytokines and IL-36R were significantly higher in AR compared with control, especially in asthmatic patients. Among the IL-36 cytokines, the expression of IL-36γ was the highest. The expression of IL-36R by eosinophils were significantly increased compared with normal controls and was up-regulated by recombinant IL-17, IL-25, IL-33 and Dermatophagoides pteronyssinus group 1. The IL-36γ promote the survival, adhesion, migration and activation of eosinophils. Human nasal epithelial cells can secrete IL-36γ after treated with recombinant IL-17, IL-25, IL-33. ConclusionsHigh expression of IL-36γ exaggerates eosinophilic inflammation in AR by promoting the survival, adhesion, and activation of eosinophils.

Overlapping Roles for Interleukin-36 Cytokines in Protective Host Defense against Murine Legionella pneumophila Pneumonia.

Legionella pneumophila causes life-threatening pneumonia culminating in acute lung injury. Innate and adaptive cytokines play an important role in host defense against L. pneumophila infection. Interleukin-36 (IL-36) cytokines are recently described members of the larger IL-1 cytokine family known to exert potent inflammatory effects. In this study, we elucidated the role for IL-36 cytokines in experimental pneumonia caused by L. pneumophila Intratracheal (i.t.) administration of L. pneumophila induced the upregulation of both IL-36α and IL-36γ mRNA and protein production in the lung. Compared to the findings for L. pneumophila-infected wild-type (WT) mice, the i.t. administration of L. pneumophila to IL-36 receptor-deficient (IL-36R-/-) mice resulted in increased mortality, a delay in lung bacterial clearance, increased L. pneumophila dissemination to extrapulmonary organs, and impaired glucose homeostasis. Impaired lung bacterial clearance in IL-36R-/- mice was associated with a significantly reduced accumulation of inflammatory cells and the decreased production of proinflammatory cytokines and chemokines. Ex vivo, reduced expression of costimulatory molecules and impaired M1 polarization were observed in alveolar macrophages isolated from infected IL-36R-/- mice compared to macrophages from WT mice. While L. pneumophila-induced mortality in IL-36α- or IL-36γ-deficient mice was not different from that in WT animals, antibody-mediated neutralization of IL-36γ in IL-36α-/- mice resulted in mortality similar to that observed in IL-36R-/- mice, indicating redundant and overlapping roles for these cytokines in experimental murine L. pneumophila pneumonia.

Interleukin-36 cytokines regulate antiviral immunity in the skin and keratinocytes

Abstract Pathogens develop immune evasion strategies that delay host immune responses. How the host has adapted counter strategies is often less clear. Herpes simplex virus (HSV) blocks inflammatory signaling from infected cells by preventing extracellular release of IL-1β. Previously, we reported that HSV infected keratinocytes retain the ability to signal danger to the surrounding tissue through secretion of IL-1α. This inflammatory signal appeared essential in vivo for early recruitment of immune cells to infected sites. Furthermore, mice deficient of the common receptor for IL-1α and IL-1β, IL-1R1, were more susceptible to lethal outcome of HSV infection. Hence, IL-1α may have evolved to counteract the HSV immune evasion mechanism targeting IL-1β. Here, the IL-1 related IL-36α, IL-36β and IL-36γ are studied. Like the IL-1 cytokines, the IL-36 proteins lack signal peptides for conventional protein secretion. The IL-36α mRNA was the principal IL-36 induced in keratinocytes by HSV-1 in vitro. Surprisingly, using the flank skin HSV-1 infection model, IL-36α knockout (KO) mice developed disease indistinguishable from that observed in wild type mice. In contrast, IL-36β KO mice progressed to more severe disease, whereas IL-36γ KO mice only developed modestly larger skin lesions. This could suggest that HSV-1 promotes retention of IL-36α in a manner resembling that restricting IL-1β activity. IL-36β on the other hand may achieve the highest degree of activity through a yet to be determined mechanism. Viral loads were elevated in skin from IL-36β KO mice. Furthermore, pre-treatment of human keratinocytes delayed progression of HSV-1 infections. These observations suggest that IL-36β regulates innate antiviral mechanisms in keratinocytes.

THE ROLE OF CYTOKINES OF INTERLEUKIN 36 FAMILY IN IMMUNOPATHOGENESIS OF PSORIASIS

Over last decade, the importance of immune mechanisms for development of psoriasis has expanded considerably. This review describes biological properties of the cytokines from the interleukin-36 (IL-36) family, and their role in pathogenesis of plaque psoriasis, generalized pustular psoriasis and psoriatic arthritis. Keratinocytes and dendritic cells (DC) are the main sources of IL-36 in the skin. Production of this cytokine is greatly enhanced by inflammation. The studies have shown that, in affected skin of psoriatic patients, an increased expression of IL-36α and IL-36γ is observed. IL-36γ can be considered a specific marker of psoriasis, which is not found in other inflammatory skin diseases (neurodermatitis, lichen planus, eczema). The levels of this cytokine correlate with severity of psoriasis and decreases after anti-TNFα therapy. High level of IL-36 cytokines in the areas of psoriatic eruptions correlates with increased concentrations of pro-inflammatory TNFα, IL-17, IL-22 and IFNγ in the skin. We present literature data on the role of IL-36RN mutation which encodes the IL-36ra receptor antagonist, playing a role in the development of generalized pustular psoriasis (GPP). Excessive activity of IL-36 agonists leading to accumulation of neutrophilic granulocytes in epidermis may be a key event in the GPP pathogenesis. The article deals with modern ideas about the role of neutrophilic granulocytes in development of chronic inflammatory processes underlying pathogenesis of psoriasis. Proteases of neutrophils (cathepsin G, elastase and proteinase-3) are potent IL-36 activating enzymes that increase activity of IL-36 cytokines up to 500 times. In this review, a new mechanism (netosis) is suggested for the role of neutrophils in immune response. During the netosis, a large number of cytokines, antimicrobial peptides, intracellular components, serine proteases are released into the extracellular space. Thus, they may be involved into initiation and maintenance of a chronic inflammatory process in psoriasis. The present information concerning a role of new IL-36 family cytokines as one of the main psoriasis mediators has opened new therapeutic goals for the treatment of this disease and development of new methods of targeted therapy. Specific blocking of IL-36R signaling, or inhibition of neutrophil proteases of cathepsin G, neutrophil elastase that activate members of the IL-36 family, is likely to be a successful strategy in the therapy of psoriasis.

Quantitative ligand and receptor binding studies reveal the mechanism of interleukin-36 (IL-36) pathway activation

IL-36 cytokines signal through the IL-36 receptor (IL-36R) and a shared subunit, IL-1RAcP (IL-1 receptor accessory protein). The activation mechanism for the IL-36 pathway is proposed to be similar to that of IL-1 in that an IL-36R agonist (IL-36α, IL-36β, or IL-36γ) forms a binary complex with IL-36R, which then recruits IL-1RAcP. Recent studies have shown that IL-36R interacts with IL-1RAcP even in the absence of an agonist. To elucidate the IL-36 activation mechanism, we considered all possible binding events for IL-36 ligands/receptors and examined these events in direct binding assays. Our results indicated that the agonists bind the IL-36R extracellular domain with micromolar affinity but do not detectably bind IL-1RAcP. Using surface plasmon resonance (SPR), we found that IL-1RAcP also does not bind IL-36R when no agonist is present. In the presence of IL-36α, however, IL-1RAcP bound IL-36R strongly. These results suggested that the main pathway to the IL-36R·IL-36α·IL-1RAcP ternary complex is through the IL-36R·IL-36α binary complex, which recruits IL-1RAcP. We could not measure the binding affinity of IL-36R to IL-1RAcP directly, so we engineered a fragment crystallizable-linked construct to induce IL-36R·IL-1RAcP heterodimerization and predicted the binding affinity during a complete thermodynamic cycle to be 74 μm The SPR analysis also indicated that the IL-36R antagonist IL-36Ra binds IL-36R with higher affinity and a much slower off rate than the IL-36R agonists, shedding light on IL-36 pathway inhibition. Our results reveal the landscape of IL-36 ligand and receptor interactions, improving our understanding of IL-36 pathway activation and inhibition.

Increased expression of the interleukin-36 cytokines in lesions of hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a recalcitrant chronic skin disease with poorly understood immunopathogenic mechanisms. Previous studies reported that the interleukin-36 (IL-36) cytokines [IL-36α, IL-36β, IL-36γ and IL-36 receptor antagonists (IL-36RA)] are important players in the pathogenesis of psoriasis (PS). We aim to determine whether the IL-36 cytokines are upregulated in patients with HS. For this purpose, we analysed local expression and systemic levels of the IL-36 cytokines in patients with HS and compared the results to healthy donors and patients with PS. Skin biopsies from healthy donors and HS and PS patients were analysed for expression of the IL-36 cytokines by immunohistochemistry and semiquantitative real-time PCR. The enzyme-linked immunosorbent assay (ELISA) was used to measure systemic levels of the IL-36 cytokines in the serum of the three donor groups. The agonists IL-36α, IL-36β and IL-36γ were found to be upregulated in HS both systemically and lesionally, while the IL-36RA was not differently regulated in comparison to healthy donors. Our findings suggest that the agonistic IL-36 isoforms are upregulated in HS. The relevance of the enhanced production of IL-36 cytokines in HS pathogenesis remains to be determined.

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling.

Pathogens deploy immune evasion strategies to successfully establish infections within their hosts. Naturally, the host responds by acquiring mechanisms to counter these strategies. There is increasing evidence that the three interleukin-36 (IL-36) cytokines, IL-36α, IL-36β and IL-36γ, play important roles in host immunity. With a focus on the skin as a target for microbial and viral invasion, the current knowledge of IL-36 functions is reviewed. Furthermore, the hypothesis that the IL-36s have evolved to counteract virulence factors is presented using viruses as an example. The IL-36s are related to IL-1α, IL-1β, IL-18, and IL-33. Numerous viruses affecting the skin have developed immune evasion strategies that neutralize IL-1α, IL-1β, or IL-18 signaling or combinations of these pathways. Through small differences in activation mechanisms and receptor utilization, it is possible that IL-36 signaling may proceed unhindered in the presence of these viral inhibitors. Thus, one physiological function of the IL-36s may be to counteract microbial immune evasion.

Interleukin-36 cytokines as countermeasures to viral immune evasion

Abstract IL-36α, IL-36β and IL-36γ engage the same receptor, IL-36R, and are related to the pro-inflammatory IL-1α, IL-1β, IL-18 and IL-33. While there is increasing evidence that the IL-36s play important roles in host immunity, the redundancy remains an enigma. Here we explore the possibility that the IL-36s have evolved to counteract viral immune evasion mechanisms. Many skin tropic viruses inhibit IL-1β and IL-18 as immune evasion prevent protein synthesis, accelerate mRNA and protein turnover, block inflammasome activation, inhibit caspase-1, trap cytokines and/or impede signaling. IL-36γ production is induced by poly(I:C); however, IL-36γ does not appear to play a significant role in the flank skin HSV-1 infection mouse model. This outcome may be due to the release of IL-36γ being dependent upon the inflammasome pathway, which is blocked by HSV-1. Similar observations were made using IL-36α KO mice. Additional data reveal that IL-1α is released in an inflammasome independent manner from HSV-1 infected keratinocytes; an event important for early recruitment of inflammatory cells to sites of HSV-1 infection in vivo. IL-36β appears to play an additional role in the skin, as IL-36β KO mice develop larger skin lesions than wildtype mice. Furthermore, the survival rate was significantly reduced. Complementary studies involving the TLR7 ligand imiquimod were performed. Imiquimod induced skin inflammation was dependent upon IL-36α, but independent of IL-36β and IL-36γ. This could suggest an important role for IL-36α in immunity against viruses that activate TLR7 yet evade immune responses targeting IL-1/IL-18 signaling, e.g., the measles virus. Our data may suggest that the IL-36 cytokines have evolved to counteract viral immune evasion.

IL‐36γ has proinflammatory effects on human endothelial cells

Interleukin-36 cytokines are predominantly expressed by epithelial cells. Significant upregulation of epidermal IL-36 is now a recognised characteristic of psoriatic skin inflammation. IL-36 is known to induce inflammatory responses in dendritic cells, fibroblasts and epithelial cells. Although vascular alterations are a hallmark of psoriatic lesions and dermal endothelial cells are well known to play a critical role in skin inflammation, the effects of IL-36 on endothelial cells are unexplored. We here show that endothelial cells including dermal microvascular cells express a functionally active IL-36 receptor. Adhesion molecules VCAM-1 and ICAM-1 are upregulated by IL-36γ stimulation, and this is reversed by the presence of the endogenous IL-36 receptor antagonist. IL-36γ-stimulated endothelial cells secrete the proinflammatory chemokines IL-8, CCL2 and CCL20. Chemotaxis assays showed increased migration of T-cells following IL-36γ stimulation of endothelial cells. These results suggest a role for IL-36γ in the dermal vascular compartment, and it is likely to enhance psoriatic skin inflammation by activating endothelial cells and promoting leucocyte recruitment.

Regulation and function of interleukin-36 cytokines in homeostasis and pathological conditions.

IL-36α, IL-36β, and IL-36γ are members of the IL-1 family of cytokines that signal through a common receptor composed of IL-36R and IL-1R/AcP to activate NF-κB and MAPKs, such as p38 and JNK, and promote inflammatory responses. IL-36Ra is a natural antagonist of the 3 IL-36 agonists that binds to IL-36R and inhibits binding of the agonistic ligands. These cytokines are expressed predominantly by epithelial cells and act on a number of cells, including immune cells, epithelial cells, and fibroblasts. Processing of the N terminus is required for full agonist or antagonist activity for all IL-36 members. The role of IL-36 has been demonstrated extensively in the skin, where it can act on keratinocytes and immune cells to induce a robust inflammatory response and is implicated strongly through functional and genetic evidence in the pathology of psoriatic disorders. Emerging data also suggest a role for this cytokine family in pulmonary physiology and pathology. Although much has been learned about the biochemistry of IL-36 and its role in various tissues, it is clear that we are at an early stage in our understanding of the full biology of these cytokines.