Functions of IKK alpha in Skin Homeostasis and Skin Tumorigenesis

Division Of Basic Sciences - Nci

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Abstract

Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) show diverse endocrine and non-endocrine manifestations initiated by self-reactive T cells due to AIRE mutation-induced defective central tolerance. A large number of APECED patients suffers from early-onset cutaneous inflammatory lesions accompanied by an infiltration of T cells and myeloid cells. The role of myeloid cells in this setting remains to be fully investigated. Here, we characterize the autoinflammatory phenotypes in the skin specimens of both APECED-like kinase-dead IKKa knockin (KA/KA) mice and APECED patients and we found a marked infiltration of autoreactive CD4 T cells, macrophages, and neutrophils; elevated uric acid levels; and increased expression of NLRP3, a major inflammasome component. Depleting autoreactive CD4 T cells or ablating Ccl2/Cxcr2 genes significantly attenuated the inflammasome activity, inflammation, and skin phenotypes in KA/KA mice. Importantly, treatment with a NLRP3 inhibitor decreased infiltration of CD4 T cells, macrophages, and neutrophils, and reduced skin phenotypes in mice. These results suggest that increased myeloid cell infiltration contributes to autoreactive CD4 T cell-mediated skin autoinflammation. Thus, our findings reveal that the combined infiltration of macrophages and neutrophils is required for autoreactive CD4 T cell-mediated skin disease pathogenesis and that NLRP3-dependent inflammasome is a novel therapeutic target for the cutaneous manifestations of autoimmune diseases.