Journal article
Genetic diversity of Collaborative Cross mice implicates FFAR3 as a target for ILC2 anti-inflammatory reprogramming
Nature communications, Vol.17(1), 1053
2026
DOI: 10.1038/s41467-025-67813-2
PMID: 41484153
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.
Details
- Title: Subtitle
- Genetic diversity of Collaborative Cross mice implicates FFAR3 as a target for ILC2 anti-inflammatory reprogramming
- Creators
- Mark Rusznak - Vanderbilt University Medical CenterShinji Toki - Vanderbilt University Medical CenterYajing Hao - University of North Carolina at Chapel HillMarc J C Todd - Vanderbilt University Medical CenterLiddy Malone - Vanderbilt University Medical CenterJulia F Goodhead - Vanderbilt University Medical CenterCatherine DuPuy - Vanderbilt University Medical CenterWeisong Zhou - Vanderbilt University Medical CenterDominique Babin - Vanderbilt University Medical CenterChristian M Warren - VA Tennessee Valley Healthcare SystemMasako Abney - Vanderbilt University Medical CenterMatthew T Stier - Vanderbilt University Medical CenterChristopher M Thomas - Vanderbilt University Medical CenterJing Li - Vanderbilt University Medical CenterJustin Jacobse - Vanderbilt University Medical CenterAndrew P Pahnke - Vanderbilt University Medical CenterMark I Petrovic - Vanderbilt University Medical CenterJacqueline-Yvonne Cephus - Vanderbilt University Medical CenterShelby N Kuehnle - Vanderbilt University Medical CenterM Wade Calcutt - Vanderbilt UniversityAllison E Norlander - Indiana University – Purdue University IndianapolisFang Yan - Vanderbilt University Medical CenterJeremy A Goettel - Vanderbilt University Medical CenterDarla R Miller - University of North Carolina at Chapel HillRachel M Lynch - University of North Carolina at Chapel HillDaniel P Cook - University of IowaDawn C Newcomb - Vanderbilt University Medical CenterFei Zou - University of North Carolina at Chapel HillR Stokes Peebles Jr - Vanderbilt University
- Resource Type
- Journal article
- Publication Details
- Nature communications, Vol.17(1), 1053
- DOI
- 10.1038/s41467-025-67813-2
- PMID
- 41484153
- NLM abbreviation
- Nat Commun
- ISSN
- 2041-1723
- eISSN
- 2041-1723
- Publisher
- Springer Nature; BERLIN
- Grant note
- R01AI111820 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) F30AI176712 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01AI124456 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) U19AI095227 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) 101BX004299 / U.S. Department of Veterans Affairs (Department of Veterans Affairs)
- Language
- English
- Electronic publication date
- 01/03/2026
- Date published
- 2026
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985116913002771
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