A7.13 Distinct expression of IL-36α, β, γ and their antagonists IL-36RA and IL-38 in psoriasis, rheumatoid arthritis (RA) and crohn’s disease (CD)

Abstract

Background and objectivesThe IL-36 family of cytokines comprises three agonists: IL-36α, IL-36β and IL-36γ, an antagonist: IL-36Ra, and IL-38: another potential IL-36 inhibitor. IL-36 agonists are highly expressed in skin and are involved in the pathogenesis of psoriasis, while antagonists limit uncontrolled inflammation. The expression and role of IL-36 cytokines in other chronic inflammatory diseases is currently debated. In this study, we compared the expression profile of IL-36 cytokines in psoriasis, RA and CD.Materials and methodsSkin, joint and colon inflammation was induced in mice. Skin, synovial and colonic biopsies from patients respectively with psoriasis, RA or CD were collected. Synovial fluids from patients with RA were also collected. These samples were analysed for cytokines expression by RT-qPCR, ELISA, immunohistochemistry and confocal microscopy. The cell sources of IL-36 cytokines were confirmed in cell cultures after stimulation with inflammatory cytokines and TLR agonists by RT-qPCR.ResultsDuring imiquimod-induced mouse skin inflammation and in human psoriasis, expression of IL-36α, γ and IL-36Ra, but not IL-36β and IL-38, was induced and correlated with Th17 cytokines (IL-17A, IL-22…). In mice with collagen-induced arthritis and in the synovium of patients with RA, IL-36α, β, γ, IL-36Ra and IL-38 were all elevated and correlated with myeloid cytokines such as CCL3, CCL4 and MCSF, but not with Th17 cytokines. In mice with dextran sulfate sodium-induced colitis and in patients with CD, only IL-36α, γ and IL-38 were induced at a relatively low level. Only a minor subgroup of patients with RA (17–29%) or CD (25%) had an elevated IL-36 agonists/antagonists ratio, versus 93% of patients with psoriasis. By IHC and in cell cultures, the different IL-36 cytokines were produced at different levels by human keratinocytes, CD68+ inflammatory macrophages, dendritic/Langerhans cells, and CD79α+ plasmocytes.ConclusionExpression of the different IL-36 cytokines is differently regulated and their cell sources are distinct. This helps to explain the different expression profiles observed in three chronic inflammatory diseases and why only a minor subgroup of RA and CD patients have an elevated IL-36 agonists/antagonists ratio. Additional studies are necessary to better identify these patients and to investigate whether they would benefit from IL-36 neutralisation.

The alterations of gene expression of interleukin‐36α and interleukin‐37 between alopecia areata patients and healthy controls

“…This higher expression of IL‐36α in AA patients might be a crucial promoter of Th1 and Th17 autoimmune responses. Similar to our results, IL‐36α gene expression was up‐regulated in psoriatic lesions and was correlated with disease severity 5 . In fact, anti‐IL‐36 receptor monoclonal antibodies repressed skin inflammation and inflammatory mediators’ expression in psoriasiform mouse model 6 .…”

Long noncoding RNA H19 alleviates inflammation in osteoarthritis through interactions between TP53, IL-38, and IL-36 receptor

“…Unsurprisingly, a number of studies have uncovered the involvement of IL-38 in several autoimmune diseases. 41 For instance, a prior study came across elevated IL-38 expression levels in mice with arthritis induced by collagen as well as in patients with RA, 42 and further suggested that IL-38 exerts anti-protective effects on cartilage and bone destruction in collagen-induced arthritis. Importantly, increased expression levels of IL-38 were previously reported in patients with RA.…”

Therapeutic potential of targeting interleukin‐1 family cytokines in chronic inflammatory skin diseases*

“…In psoriasis, IL‐36 cytokines influence the cornification processes in the epidermis by acting on keratinocytes, induce the production of Th17‐ and Th1‐polarizing cytokines by myeloid dendritic cells and macrophages, and potently sustain neutrophil recruitment. In lesional psoriatic skin, IL‐36α, IL‐36γ and IL‐36Ra are indeed highly expressed 70,84 . Conversely, the antagonist IL‐38 is downregulated 85 .…”

“…The three splice variants of IL‐36 (IL‐36α, IL‐36β and IL‐36γ) are potent proinflammatory cytokines, mainly produced in barrier sites of the body (cutaneous, bronchial and intestinal epithelium) 69 . In the skin, IL‐36γ is predominantly expressed in epidermal keratinocytes 70,71 . These cytokines play a first‐line defensive role against exogenous insults and contribute to maintaining cutaneous homeostasis.…”