Genetic diversity of Collaborative Cross mice reveals 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 creates 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 reprogramming is mediated by epidermal growth factor receptor (EGFR) upregulation. We showed that FFAR3's anti-inflammatory effect is conserved in human ILC2s, making it a potential therapeutic target for Type 2 inflammation.