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

Xinyi Qi,Jinxin Qiu,Yan Ji,Qi Yang,Liming Sun,Jun Qin,Ju Qiu,Jiali Chang,Guoliang Cui,Qian Chai

doi:10.1038/s41385-020-0317-3

Abstract

Group 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.

Highlights

Group 3 innate lymphoid cells (ILC3s) belong to the ILC lineages, which are composed of subsets of ILC3s that lack T- and B-cell antigen specific receptors.[1,2,3] ILCs are abundantly present in mucosal tissues and play important roles in the initiation, progression, and resolution of inflammation
When analyzing the functional subsets of ILC3s, we observed a reduction in the proportion of NKp46+ILC3s among Lin− cells and absolute numbers of NKp46+ILC3s in the small intestinal lamina propria lymphocytes (LPLs) of Smarca4ΔILC3 mice, whereas the percentages and numbers of NKp46−ILC3s were increased in both small and large intestinal LPLs of Smarca4ΔILC3 mice compared with control group (Fig. 1a, d, e)
We identified statistically differential open chromatin regions (OCRs) in wild-type and Brg1-deficient ILC3s respectively according to DEseq[2] analysis with a cutoff value of 1.5-fold (Fig. 7a). 10,470 peaks were more accessible in wild-type ILC3s and were identified as “WT-ILC3OCRs”, whereas only 5064 “Brg1-KO-ILC3-OCRs” were found (Fig. 7a and Supplementary Data 2)

Summary

Introduction

Group 3 innate lymphoid cells (ILC3s) belong to the ILC lineages, which are composed of subsets of ILC3s that lack T- and B-cell antigen specific receptors.[1,2,3] ILCs are abundantly present in mucosal tissues and play important roles in the initiation, progression, and resolution of inflammation. ILCs mirror T helper (Th) cells in the expression of transcription factors and functional cytokines.[1] ILC3s are similar to Th17 cells, which are featured by the expression of retinoic acid-related orphan receptor gamma t (RORγt) and production of IL-17 and IL-22.3 In both humans and mice, ILC3s are found to be localized in the intestinal lamina propria and function as “double-edge sword” in intestinal inflammatory diseases.[4] On one hand, ILC3s are important for immune defense against intestinal bacterial and viral infections.[5,6,7] On the other hand, ILC3s have been shown to be pathogenic in innate colitis.[8,9] The dual effect of ILC3s in intestinal inflammation is partially mediated through differential functions of cytokines produced by ILC3s. Both IL-17 and IL-22 are important for maintenance of intestinal epithelial integrity by facilitating the regeneration of IECs.[14,15] overt production of IL-17 and IL-22 could result in accumulation of neutrophils, which facilitates pathogen clearance but exacerbates tissue damage.[9,16] Besides IL-17 and IL-22, IFN-γ produced by ILC3s has been suggested to contribute to the pathogenesis of innate colitis.[8,9,17]

Methods

Results

Conclusion