Background/Purpose: The IL-36 family of cytokines comprises three agonists, IL-36α, IL-36β and IL-36g, an antagonist IL-36Ra, as well as 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 Crohn’s disease (CD).     

Methods: Skin, joint and colon inflammation was induced in mice according to standard protocols. Skin, synovial and colonic biopsies from patients respectively with psoriasis (n=15), RA (n=21) or CD (n=16) were collected with corresponding control samples. Synovial fluids from patients with RA (n=30) or osteoarthritis (n=29) were also collected. These samples were analyzed for cytokine expression by RT-qPCR, ELISA, multiparametric Luminex assays, 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.

Results: During imiquimod-induced mouse skin inflammation and in human psoriasis, expression of IL-36α, g and IL-36Ra, but not IL-36β and IL-38, was induced and correlated with Th17 cytokines (IL-17A, IL-22, IL-23, CCL20), IL-1β, Oncostatin M, IFNg and IL-8. In mice with collagen-induced arthritis and in the synovium of patients with RA, IL-36α, β, g, IL-36Ra and IL-38 were all elevated and correlated with IL-1β, myeloid cytokines such as CCL3, CCL4 and MCSF, but not with Th17 cytokines, TNFα or IL-6. In mice with dextran sulfate sodium-induced colitis and in patients with CD, only IL-36α, g 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. Endothelial cells and CD55⁺ fibroblasts could also participate, but enterocytes were poor producers.

Figure: Proposed model for the distinct expression of IL-36 cytokines in psoriasis versus RA.

Conclusion : Expression 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 neutralization.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/distinct-expression-of-il-36i%c2%b1-i%c2%b3-and-their-antagonists-il-36ra-and-il-38-in-psoriasis-rheumatoid-arthritis-and-crohns-disease/