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

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.

Setd2 determines distinct properties of intestinal ILC3 subsets to regulate intestinal immunity

“…The isolation of LPLs was done as previously described (Qi et al, 2021). In brief, the large and small intestines were dissected.…”

“…At an early stage of life upon microbiota colonization, NKp46 + ILC3s could be differentiated from the DN ILC3s under the control of master transcription factor T-bet, which is regulated by the activation of Notch signaling (Chea et al, 2016;Klose et al, 2013;Rankin et al, 2013;Sciume et al, 2012;Viant et al, 2016). Importantly, the differentiation of NKp46 + ILC3s requires accessibility of chromatin at Tbx21 promoter dependent on Brg1, ATPase component of mammalian BRG1/BRM-associated factor complex (Qi et al, 2021). Inflammatory cytokines affect the generation of NKp46 + ILC3s and could cause further conversion of NKp46 + ILC3s to ILC1s (Bernink et al, 2015;Goc et al, 2021;Klose et al, 2013;Vonarbourg et al, 2010).…”

Innate Lymphoid Cells and Intestinal Inflammatory Disorders

“…A catalytic subunit of the mammalian chromatin remodeling BAF complex Brg1 (encoded by brahma-related gene 1) is known to regulate the development and function of various immune cells. When Brg1 is specifically deleted in ILC3s, the conversion of NKp46 − ILC3s to NKp46 + ILC3s was blocked because of the failure of T-bet upregulation in NKp46 − ILC3s [95]. Strikingly, Brg1 −/− Rag1 −/− ILC3s produce increased amounts of GM-CSF and develop spontaneous colitis [95].…”

“…When Brg1 is specifically deleted in ILC3s, the conversion of NKp46 − ILC3s to NKp46 + ILC3s was blocked because of the failure of T-bet upregulation in NKp46 − ILC3s [95]. Strikingly, Brg1 −/− Rag1 −/− ILC3s produce increased amounts of GM-CSF and develop spontaneous colitis [95].…”

Effect of the Microbiome on Intestinal Innate Immune Development in Early Life and the Potential Strategy of Early Intervention

“…A considerable percentage of the lymphoid progenitor was found in the 8-week fetal intestine, which indicated that the intestine is an ILC-rich organ at fetal age, and ILC3 is a domain in the intestinal ILC family around week 12 ( 78 ). ILCs began working before the adaptive system has fully developed ( 79 ), early life is an important period for ILC maturation, and absolute ILC3 numbers increase dramatically from neonates to 14 days in mice ( 80 ). During the period of weaning, the proportion of phospho-signal transducer and activator of transcription 3 (pSTAT3) + ILC3 significantly increases, which indicates the activation of ILC3, and this phenomenon depends on IL-23 ( 79 ).…”