Genetic diversity of Collaborative Cross mice implicates FFAR3 as a target for ILC2 anti-inflammatory reprogramming.

Mark Rusznak; Shinji Toki; Yajing Hao; Marc J C Todd; Liddy Malone; Julia F Goodhead; Catherine DuPuy; Weisong Zhou; Dominique Babin; Christian M Warren; Masako Abney; Matthew T Stier; Christopher M Thomas; Jing Li; Justin Jacobse; Andrew P Pahnke; Mark I Petrovic; Jacqueline-Yvonne Cephus; Shelby N Kuehnle; M Wade Calcutt; Allison E Norlander; Fang Yan; Jeremy A Goettel; Darla R Miller; Rachel M Lynch; Daniel P Cook; Dawn C Newcomb; Fei Zou; R Stokes Peebles

doi:10.1038/s41467-025-67813-2

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Genetic diversity of Collaborative Cross mice implicates FFAR3 as a target for ILC2 anti-inflammatory reprogramming.

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Abstract

Pulmonary group 2 innate lymphoid cells (ILC2s) are key drivers of Type 2 inflammation in diseases like asthma, yet the molecular mechanisms regulating their function are incompletely understood. Using the genetically diverse Collaborative Cross (CC) mouse panel, we mapped a quantitative trait locus (QTL) that governs ILC2 prevalence in the lung after aeroallergen exposure. This QTL induces a large population of ILC2s in the lung that are resistant to activation and have diminished Type 2 effector function. We identified free-fatty acid receptor 3 (Ffar3) as a gene responsible for this effect and demonstrated that FFAR3 signaling reprograms ILC2s to an anti-inflammatory state by promoting their survival, reducing Type 2 cytokine production, and enhancing IL-10 expression. This anti-inflammatory state is dependent on IL-2 signaling, is characterized by decreased ST2 expression, and is distinct from previously described IL-10-producing ILC2 phenotypes. FFAR3-dependent reprogramming is mediated by epidermal growth factor receptor (EGFR) upregulation, and FFAR3's anti-inflammatory effect is partially conserved in human ILC2s.

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Animals Receptors, G-Protein-Coupled Mice Lymphocytes Quantitative Trait Loci Humans Lung Immunity, Innate Collaborative Cross Mice Interleukin-10 Inflammation Genetic Variation ErbB Receptors Signal Transduction Asthma Male Female Mice, Inbred C57BL Journal Article

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Mark Rusznak, Shinji Toki, Yajing Hao, Marc J C Todd, Liddy Malone, Julia F Goodhead, Catherine DuPuy, Weisong Zhou, Dominique Babin, Christian M Warren, Masako Abney, Matthew T Stier, Christopher M Thomas, Jing Li, Justin Jacobse, Andrew P Pahnke, Mark I Petrovic, Jacqueline-Yvonne Cephus, Shelby N Kuehnle, M Wade Calcutt, Allison E Norlander, Fang Yan, Jeremy A Goettel, Darla R Miller, Rachel M Lynch, Daniel P Cook, Dawn C Newcomb, Fei Zou, R Stokes Peebles. 2026-01-03. Genetic diversity of Collaborative Cross mice implicates FFAR3 as a target for ILC2 anti-inflammatory reprogramming.. https://doi.org/10.1038/s41467-025-67813-2

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