Staphylococcus aureus skin colonization promotes SLE-like autoimmune inflammation via neutrophil activation and the IL-23/IL-17 axis

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by inflammation of various organs with unknown etiology. Environmental factors and genetic factors are thought to play essential roles in the pathogenesis of SLE. The microbiota in the nasal cavity and gut are involved in SLE development, but the influence of skin microbiota is still unclear. Here, we demonstrated that epithelial cell-specific IκBζ-deficient (NfkbizΔK5) mice showed spontaneous skin inflammation with increased abundance of Staphylococcus aureus. With epicutaneous S. aureus application, NfkbizΔK5 mice developed SLE-associated autoantibodies and glomerulonephritis with IgG deposition. Epicutaneous S. aureus application significantly increased staphylococcal colonization on the skin of NfkbizΔK5 mice with reduced expression of several antimicrobial peptides in the skin. This staphylococcal skin colonization promoted caspase-mediated keratinocyte apoptosis and neutrophil activation, inducing the IL-23/IL-17 immune response by activating dendritic cells and T cells. Furthermore, the subcutaneous administration of anti-IL-23p19 and anti-IL-17A antibodies alleviated the systemic autoimmune response. Taken together, these findings underscore epithelial-immune crosstalk disturbances caused by skin dysbiosis as an essential mediator inducing autoimmune diseases.