Targeting Chemokine Receptors CCR6 and CXCR2 in A Murine Model Of IL-36a-Induced Pustular Psoriasis

Abstract

Abstract Several types of psoriasiform dermatitis are associated with increased IL-36 cytokine activity in the skin. A rare but severe psoriasis-like disorder, generalized pustular psoriasis (GPP), is linked to loss-of-function mutations in the gene encoding IL-36RA, an important negative regulator of IL-36 signaling. To understand the effects of IL-36 dysregulation in a mouse model, we studied skin inflammation induced by intradermal injections of pre-activated IL-36α. This type of inflammation was characterized by markedly increased total skin thickness and epidermal thickness. The inflammation was accompanied by increased concentrations of CCR6 and CXCR2 ligand chemokines in the skin, and large accumulations of CD4 T cells, neutrophils, and inflammatory DC. The accumulated inflammatory subsets in IL-36α-treated skin all expressed either CCR6 or CXCR2 to some extent, prompting the hypothesis that increased CCR6 and CXCR2 ligand concentrations in IL-36α-treated skin might constitute a viable target for relieving inflammation in this model. We found that the orally bioavailable small molecule CCR6/CXCR2 antagonist CCX624 did indeed reverse inflammatory cell accumulation in skin, as well as decrease total skin thickness and epidermal thickness. CCX624 was effective in both prophylactic and therapeutic dosing regimens. CCX624 treatment was more effective than saturating doses of anti-TNFα or anti-IL17RA, which are used in the clinic for treating GPP as first or second line treatments (respectively). These findings put CCR6 and CXCR2 forward as novel targets for a mechanistically distinct therapeutic approach for inflammatory skin diseases involving dysregulated IL-36 signaling, such as GPP.