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 American APECED patients suffer 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. In this study, we characterize the autoinflammatory phenotypes in the skin of both APECED-like kinase-dead Ikka knockin (KA/KA) mice and APECED patients. We found a marked infiltration of autoreactive CD4 T cells, macrophages, and neutrophils; elevated uric acid; and increased 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 an NLRP3 inhibitor reduced skin phenotypes and decreased infiltration of CD4 T cells, macrophages, and neutrophils. 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 the NLRP3-dependent inflammasome is a novel therapeutic target for the cutaneous manifestations of autoimmune diseases.