Regulation of ILC2s by Brg1

The chromatin status fluctuates with effector and memory group 2 innate lymphoid cell (ILC2) responses. How this intricate coordination affects allergic lung inflammation remains unclear. Here, we report that during papain-induced lung inflammation, the expression of chromatin remodeler Brg1 is upregulated by IL-33 in ILC2s, accompanied with more open chromatin regions having increased accessibility. Brg1 expression is also upregulated in asthma patients’ ILC2s. Ablating Brg1 constrains ILC2 expansion and ameliorates both acute and alarmin-rechallenged secondary lung inflammation. Mechanistically, Brg1 imprints the chromatin landscape favoring aerobic glycolysis, the metabolic process reinforced in effector and memory ILC2s, to facilitate ILC2 expansion. Particularly, Brg1-augmented Hif1a enhancer accessibility is a sustained epigenetic signature in memory ILC2s inherited from effector ILC2s, and Hif1a enhances effector and memory ILC2 responses. Pharmacological inhibition of Brg1, rather than dexamethasone treatment, in acute phase is sufficient to alleviate secondary lung inflammation, highlighting Brg1 as a promising therapeutic target.