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

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Pulmonary group 2 innate lymphoid cells (ILC2s) drive Type 2 inflammation in asthma.
• Mechanisms regulating ILC2 function remain poorly understood.

Purpose of the Study:

• Identify genetic factors controlling lung ILC2s after aeroallergen exposure.
• Elucidate the molecular mechanisms of ILC2 reprogramming by free-fatty acid receptor 3 (FFAR3).

Main Methods:

• Utilized the Collaborative Cross (CC) mouse panel to map quantitative trait loci (QTLs).
• Investigated the role of FFAR3 in ILC2 function and reprogramming.
• Assessed cytokine production, cell survival, and receptor expression (ST2, EGFR).
• Examined the conservation of FFAR3 effects in human ILC2s.

Main Results:

• A QTL associated with ILC2 prevalence was mapped in the lung.
• FFAR3 was identified as the responsible gene, inducing resistant, hypo-functional ILC2s.
• FFAR3 signaling promotes ILC2 survival, reduces Type 2 cytokines, and enhances IL-10 production.
• This reprogramming is IL-2 dependent, decreases ST2, upregulates EGFR, and is partially conserved in humans.

Conclusions:

• FFAR3 signaling reprograms ILC2s into an anti-inflammatory phenotype via IL-2-dependent EGFR upregulation.
• This mechanism offers novel therapeutic targets for Type 2 inflammatory lung diseases.