Genetic diversity of Collaborative Cross mice implicates FFAR3 as a target for ILC2 anti-inflammatory reprogramming
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.
Authors
- Marc J. C. Todd
- Christian M. Warren
- Allison E. Norlander (ORCID: https://orcid.org/0000-0002-9357-485X)
- Mark Rusznak
- Justin Jacobse (ORCID: https://orcid.org/0000-0002-1899-0319)
- Weisong Zhou (ORCID: https://orcid.org/0000-0002-4419-2302)
- Jeremy A. Goettel (ORCID: https://orcid.org/0000-0002-0749-2357)
- Shinji Toki (ORCID: https://orcid.org/0000-0003-4379-9118)
- Shelby N Kuehnle (ORCID: https://orcid.org/0009-0005-6919-0038)
- Masako Abney
- Dawn C. Newcomb (ORCID: https://orcid.org/0000-0003-2592-9433)
- Catherine Dupuy (ORCID: https://orcid.org/0000-0002-3947-3580)
- Darla R. Miller (ORCID: https://orcid.org/0000-0002-0781-7254)
- Matthew T. Stier (ORCID: https://orcid.org/0000-0003-3928-1682)
- Liddy Malone
- Jacqueline-Yvonne Cephus (ORCID: https://orcid.org/0000-0002-4691-4014)
- Rachel Lynch (ORCID: https://orcid.org/0000-0001-8164-0744)
- Jing Li
- Andrew P Pahnke (ORCID: https://orcid.org/0009-0000-2761-369X)
- Yan Fang
- Yajing B. Hao
- Fei Zou
- Christopher M. Thomas
- M. Wade Calcutt
- Dominique Babin
- Julia F. Goodhead
- Mark I. Petrovic
- R. Stokes Peebles
- Daniel P. Cook
Institutions
- University of North Carolina at Chapel Hill (US)
- University of Iowa (US)
- Vanderbilt University (US)
- VA Tennessee Valley Healthcare System (US)
- Indiana University – Purdue University Indianapolis (US)
- Vanderbilt University Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-01-03
- DOI
- https://doi.org/10.1038/s41467-025-67813-2
- Primary Topic
- IL-33, ST2, and ILC Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00