| Title: |
Genetic diversity of Collaborative Cross mice implicates FFAR3 as a target for ILC2 anti-inflammatory reprogramming |
| Authors: |
Rusznak, Mark; Toki, Shinji; Hao, Yajing; Todd, Marc J. C.; Malone, Liddy; Goodhead, Julia F.; DuPuy, Catherine; Zhou, Weisong; Babin, Dominique; Warren, Christian M.; Abney, Masako; Stier, Matthew T.; Thomas, Christopher M.; Li, Jing; Jacobse, Justin; Pahnke, Andrew P.; Petrovic, Mark I.; Cephus, Jacqueline-Yvonne; Kuehnle, Shelby N.; Calcutt, M. Wade; Norlander, Allison E.; Yan, Fang; Goettel, Jeremy A.; Miller, Darla R.; Lynch, Rachel M.; Cook, Daniel P.; Newcomb, Dawn C.; Zou, Fei; Peebles, R. Stokes, Jr. |
| Contributors: |
Anatomy, Cell Biology and Physiology, School of Medicine |
| Source: |
PMC |
| Publisher Information: |
Springer Nature |
| Publication Year: |
2026 |
| Collection: |
Indiana University - Purdue University Indianapolis: IUPUI Scholar Works |
| Subject Terms: |
Innate lymphoid cells; Immunogenetics; Chronic inflammation; Mucosal immunology; Asthma |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
Nature Communications; https://hdl.handle.net/1805/54028 |
| Availability: |
https://hdl.handle.net/1805/54028 |
| Rights: |
Attribution 4.0 International ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: |
edsbas.F1DB1C1E |
| Database: |
BASE |