Brg1-imprinted chromatin status controls effector and memory group 2 innate lymphoid cell metabolism to exacerbate allergic lung inflammation - 05/01/26
, Jun Qin, PhD a , Ju Qiu, PhD a, ⁎ Graphical abstract |
Abstract |
Background |
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.
Objective |
We examined how the chromatin remodeler brahma-related gene 1 (Brg1) regulates ILC2s in allergic lung inflammation.
Methods |
Acute lung allergic inflammation was induced with papain in wild-typ e, Il5 Cre/+ Smarca4 flox/flox ( Smarca4 f/f) , Il5 Cre/+ Hif1a f/f , and Il5 Cre/+ Ldha f/f mice. Secondary lung inflammation was induced with low-dose IL-33 in papain-primed Il5 Cre/+ Smarca4 f/f mice. ATAC-Seq, RNA sequencing, and Brg1 CUT & Tag analyses were performed on naive ILC2s, effector ILC2s (ILC2 eff ), memory ILC2s (ILC2 mem ), IL-33–challenged Brg1-deficient ILC2s, Brg1-deficient ILC2 mem , and human ILC2s treated with or without the Brg1 inhibitor Compound 14. ILC2 metabolism was analyzed by 13 C glucose isotype tracing and metabolic flux, Seahorse, and SCENITH assays. Compound 14 was used to treat mouse and humanized mouse models of allergic lung inflammation.
Results |
Brg1 expression was upregulated in asthma patients’ ILC2s and was induced by IL-33. Brg1 promoted IL-5 + and IL-13 + ILC2 expansion and exacerbated both acute and secondary lung inflammation. Brg1 imprinted the chromatin landscape favoring aerobic glycolysis, the metabolic process reinforced in ILC2 eff and ILC2 mem . Brg1-augmented Hif1a enhancer accessibility was a sustained epigenetic signature in ILC2 mem inherited from ILC2 eff , and Hif1α enhanced ILC2 eff and ILC2 mem responses. Pharmacologic inhibition of Brg1, rather than dexamethasone treatment, in acute phase alleviated secondary lung inflammation.
Conclusion |
Brg1 promotes the expansion of pathogenic ILC2 eff and ILC2 mem and exacerbates allergic lung inflammation. Mechanistically, Brg1 increases the chromatin accessibility and transcription of Hif1a and Ldha, key factors reinforcing ILC2 glycolysis metabolism.
Le texte complet de cet article est disponible en PDF.Key words : Group 2 innate lymphoid cell (ILC2), Brg1, allergic lung inflammation, ILC2 memory, chromatin accessibility, glycolysis
Abbreviations used : ATAC-Seq, BAF, BALF, BRG, BRM, cDNA, Comp14, Ctrl, CUT&Tag, DMEM, DMSO, ECAR, GC/MS, GEO, gRNA, GSEA, Hif1a/α, ILC2, ILC2 eff , ILC2 mem , ILC2 nav , KO, LDHA, Lin, MIG, mRNA, mSWI/SNF, OCR, OXPHOS, PAS, PBS, rh, RNA-Seq, SBE-β-CD, SCENITH, SEM, Smarca4, WT
Plan
| Jupei Tang and Hanxiao Sun contributed equally to this article, and both should be considered first authors. Ju Qiu, Jun Qin, and Jinxin Qiu contributed equally to this article, and all should be considered senior authors. |
Vol 157 - N° 1
P. 155-175 - janvier 2026 Retour au numéro
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