Psoriasis vulgaris (PV) results from activation of IL-23/Th17 immune pathway and is further amplified by skin responses. Among skin derived pro-inflammatory cytokines, IL-36 family members are highly upregulated in PV patients and play a critical role in general pustular psoriasis. However, there is scant data showing crosstalk between the IL-23 and IL-36 pathways in PV. Herein we interrogate if functional inhibition of IL-36 receptor (IL-36R) in the IL-23-induced mouse models of psoriasiform dermatitis drives down the skin inflammation. Anti-IL-36R antibodies (mAbs) were validated in vitro by inhibiting IL-36 induced secretion of mouse CXCL1 from NIH 3T3 cells. In vivo antibody target engagement was validated by inhibition of CXCL1 production in an acute model of IL-36 systemic injection. In addition, anti-IL-36R mAbs were able to inhibit tissue inflammation and inflammatory gene expression in an IL-36 ear injection model of psoriasiform dermatitis demonstrating adequate target coverage in the ear skin. To elucidate the possible role of IL-36 signaling in IL-23/Th17 pathway we tested the ability of anti-IL-36R mAbs to inhibit skin inflammation in both IL-23 ear injection and IL-23 mini-circle mouse models. We show that inhibiting the IL-36 pathway results in significant but modest attenuation of skin thickening, inflammatory cell infiltration and psoriasis-relevant gene expression in both models. Taken together, our data suggests a role for IL-36 signaling in the IL-23/Th17 signaling axis in PV.

IL-36 receptor antagonistic antibodies inhibit inflammatory response in IL-23 model of psoriasiform dermatitis