Brg1 restrains the pro-inflammatory properties of ILC3s and modulates intestinal immunity

Abstract

AbstractGroup 3 innate lymphoid cells (ILC3s), a subset of the innate lymphoid cells, are abundantly present in the intestine and are crucial regulators of intestinal inflammation. Brg1 (Brahma-related gene 1), a catalytic subunit of the mammalian SWI-SNF-like chromatin-remodeling BAF complex, regulates the development and function of various immune cells. Here, by genetic deletion of Brg1 in ILC3s (Smarca4ΔILC3), we prove that Brg1 supports the differentiation of NKp46+ILC3s by promoting the T-bet expression in NKp46−ILC3s, which facilitates the conversion of NKp46−ILC3s to NKp46+ILC3s. Strikingly, Smarca4ΔILC3 mice of the Rag1−/− background develop spontaneous colitis accompanied with increased GM-CSF production in ILC3s. By construction of a mixed bone marrow chimeric system, we demonstrate that Brg1 enhances T-bet and inhibits GM-CSF expression in ILC3s through a cell-intrinsic manner. Blockade of GM-CSF ameliorates colitis in Rag1−/−Smarca4ΔILC3 mice, suggesting that the suppression of GM-CSF production from ILC3s by Brg1 serves as a critical mechanism for Brg1 to restrain intestinal inflammation. We have further demonstrated that Brg1 binds to the Tbx21 and Csf2 gene locus in ILC3s, and favors the active and repressive histones modifications on gene locus of Tbx21 and Csf2 respectively. Our work reveals the essential role of Brg1 in intestinal immunity by regulating ILC3s.