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<p>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 (<i>Ffar3</i>) 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月3日

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  • Mark Rusznak,
  • Shinji Toki,
  • Yajing Hao,
  • Marc J. C. Todd,
  • Liddy Malone,
  • Julia F. Goodhead,
  • Catherine DuPuy,
  • Weisong Zhou,
  • Dominique Babin,
  • Christian M. Warren,
  • Masako Abney,
  • Matthew T. Stier,
  • Christopher M. Thomas,
  • Jing Li,
  • Justin Jacobse,
  • Andrew P. Pahnke,
  • Mark I. Petrovic,
  • Jacqueline-Yvonne Cephus,
  • Shelby N. Kuehnle,
  • M. Wade Calcutt,
  • Allison E. Norlander,
  • Fang Yan,
  • Jeremy A. Goettel,
  • Darla R. Miller,
  • Rachel M. Lynch,
  • Daniel P. Cook,
  • Dawn C. Newcomb,
  • Fei Zou,
  • R. Stokes Peebles Jr

摘要

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.