# Genetic diversity of Collaborative Cross mice implicates FFAR3 as a target for ILC2 anti-inflammatory reprogramming

## TL;DR

This study shows that genetic diversity in mice affects ILC2 function, identifying FFAR3 as a key gene that reprograms these cells to reduce inflammation in the lungs.

## Contribution

The study identifies FFAR3 as a novel target for reprogramming ILC2s to an anti-inflammatory state during lung inflammation.

## Key findings

- Ffar3 is responsible for a QTL that reduces ILC2 activation and Type 2 effector function in the lung.
- FFAR3 signaling promotes ILC2 survival, reduces cytokine production, and increases IL-10 expression.
- FFAR3-dependent reprogramming involves EGFR upregulation and is partially conserved in human ILC2s.

## 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.

Pulmonary type 2 inflammation is associated with type 2 innate lymphoid cells. Here the authors use the Collaborative Cross mouse panel to show that ILC2 abundance during type 2 lung inflammation is different across the panel and identify free-fatty acid receptor 3 (Ffar3) as a gene responsible and show cytokine and ILC2 functional changes.