IκBζ controls IL-17-triggered gene expression program in intestinal epithelial cells that restricts colonization of SFB and prevents Th17-associated pathologies

Abstract

Control of gut microbes is crucial for not only local defense in the intestine but also proper systemic immune responses. Although intestinal epithelial cells (IECs) play important roles in cytokine-mediated control of enterobacteria, the underlying mechanisms are not fully understood. Here we show that deletion of IκBζ in IECs in mice leads to dysbiosis with marked expansion of segmented filamentous bacteria (SFB), thereby enhancing Th17 cell development and exacerbating inflammatory diseases. Mechanistically, the IκBζ deficiency results in decrease in the number of Paneth cells and impairment in expression of IL-17-inducible genes involved in IgA production. The decrease in Paneth cells is caused by aberrant activation of IFN-γ signaling and a failure of IL-17-dependent recovery from IFN-γ-induced damage. Thus, the IL-17R–IκBζ axis in IECs contributes to the maintenance of intestinal homeostasis by serving as a key component in a regulatory loop between the gut microbiota and immune cells.

The central inflammatory regulator IκBζ: induction, regulation and physiological functions

“…IκBζ deficiency caused Paneth cell numbers to decline and IL-17-inducible genes that are involved in IgA synthesis to be expressed less efficiently. The loss of Paneth cell integrity and reduced IgA secretion are critical for microbiota dysregulation ( 146 ). Autoimmune disorders: NFKBIZ expression was found to be upregulated in both T cells and B cells on the basis of scRNA-seq data obtained from chronic antibody-mediated rejection (cABMR) patients ( 147 ).…”