Introduction: Psoriasis is a chronic inflammatory skin disease triggered by TH17 immunity. Interleukin-36 (IL-36) subfamily members, including IL-36α, IL-36ß, IL-36γ and IL-36Ra, are mainly expressed in the skin and are thought to be key players in psoriatic inflammation. IL-38, a new IL-36 subfamily cytokine, can antagonize IL-36R and other IL-1 family receptors, thereby inhibiting Th17 cytokines production. However, it is still unknown whether IL-38, especially the mature cytokine, has a role in psoriatic inflammation.
Method: In this study, the IMQ-induced psoriasis mouse model was applied to IL-38-deficient (IL-38 KO) mice and wildtype (WT) mice with or without mature IL-38 (IL-38 7-152aa) treatment. Before and after the treatment, mice were sacrificed at different time points. Disease severity was evaluated by clinical scoring. Immune cell composition of the skin was analyzed by flow cytometry. Cytokines profiles were determined by CBA (Cytometric Bead Array) and quantitative PCR. Moreover, skin histology was performed by Phenoptics to analyze epidermal regeneration and immune cell infiltrates.
Results: IL-38 KO mice showed delayed resolution of IMQ-induced skin inflammation, which was dependent on overshooting TH17 inflammation. At early time-points (day 3) IL-38 KO mice expressed increased IL-17A, IL-23 and IL-1ß compared to WT mice, which was followed by an increased neutrophil influx on day5. Furthermore, IL-38 KO mice exhibited delayed keratinocyte regeneration and markedly enhanced scaling. After the treatment with IL-38 7-152aa, scaling as well as markers of TH17 activity were suppressed compared to control mice.
Conclusion: Our findings suggest that IL-38 has a pro-resolving role in psoriatic inflammation by suppressing IL-17A expression and promoting keratinocytes differentiation in mouse epidermis. Our findings indicate therapeutic potential of IL-38 in inflammatory skin diseases such as psoriasis.