2025
J Exp Med. 2025 Jul 7;222(7):e20241671. doi: 10.1084/jem.20241671. Epub 2025 May 28.
Functional targeting of ILC2s and ILC3s reveals selective roles in intestinal fibrosis and homeostasis
School of Biomedical Engineering, University of British Columbia , Vancouver, Canada. Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada. Department of Pathology and Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. The Department of Medical Genetics, University of British Columbia, Vancouver, Canada. The Center for Heart Lung Innovation, St Paul's Hospital , Vancouver, Canada.
Service type: Stock strains
Abstract
Innate lymphoid cells (ILCs) are long-lived, tissue-resident cell analogs to T helper subsets that lack antigen-specific receptors. Understanding the roles of specific ILCs in chronic inflammation and fibrosis has been limited by inadequate tools for selective targeting. Here, we used Il17rb-CreERT2-eGFP and Rorc-Cre strains to selectively delete RORα in ILC2s and ILC3/Th17 cells, respectively. RORα deletion in ILC2s caused significant loss of gastrointestinal ILC2s, increased ILC3 abundance, elevated Th17-type responses, and heightened susceptibility to Crohn's disease-like fibrosis. Conversely, RORα deletion in ILC3/Th17 cells reduced IL-17 production, protecting against fibrosis. Using isolithocholic acid (isoLCA), a microbial secondary bile acid and RORγt inverse agonist, we confirmed the role of ILC3s/Th17 cells in fibrosis. In RORγt reporter and Th17-deficient Rag1-/- mice, isoLCA reduced IL-17 production by ILC3s and attenuated intestinal fibrosis by dampening RORγt-dependent ILC3/Th17 responses. These findings reveal a novel interplay between ILC2s and ILC3s in gut homeostasis and demonstrate the therapeutic potential of targeting RORγt in ILC3s as a strategy for preventing fibrosis.
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