A stromal progenitor and ILC2 niche promotes muscle eosinophilia and fibrosis-associated gene expression

Despite the well-accepted view that chronic inflammation contributes to the pathogenesis of Duchenne muscular dystrophy (DMD), the function and regulation of eosinophils remain an unclear facet of type II innate immunity in dystrophic muscle. We report the observation that group 2 innate lymphoid cells (ILC2s) are present in skeletal muscle and are the principal regulators of muscle eosinophils during muscular dystrophy. Eosinophils were elevated in DMD patients and dystrophic mice along with interleukin (IL)-5, a major eosinophil survival factor that was predominantly expressed by muscle ILC2s. We also find that IL-33 was upregulated in dystrophic muscle and was predominantly produced by fibrogenic/adipogenic progenitors (FAPs). Exogenous IL-33 and IL-2 complex (IL-2c) expanded muscle ILC2s and eosinophils, decreased the cross-sectional area (CSA) of regenerating myofibers, and increased the expression of genes associated with muscle fibrosis. The deletion of ILC2s in dystrophic mice mitigated muscle eosinophilia and impaired the induction of IL-5 and fibrosis-associated genes. Our findings highlight a FAP/ILC2/eosinophil axis that promotes type II innate immunity, which influences the balance between regenerative and fibrotic responses during muscular dystrophy. [Display omitted] •Muscle ILC2s are activated and increased in diseased muscle•IL-33 is predominantly expressed by FAPs and expands muscle ILC2s•ILC2s drive muscle eosinophilia in an IL-5-dependent manner•Expansion of ILC2s promotes transcription of genes associated with muscle fibrosis Immune cells that comprise type II innate immunity coalesce to regulate tissue repair and fibrosis. Kastenschmidt et al. report that ILC2s reside in skeletal muscle, are activated in muscular dystrophy, and promote muscle eosinophilia. Stromal progenitors expressed IL-33, which expanded ILC2s and promoted a transcriptional program associated with muscle fibrosis.