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
2026-01-04
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.