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

Cell Rep. 2021 Apr 13;35(2):108997. doi: 10.1016/j.celrep.2021.108997.


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.

Keywords: ILC2; ST2; chemokines; eosinophils; fibro/adipogenic progenitors; interleukin-33; interleukin-5; muscle inflammation; muscular dystrophy; type II innate immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation
  • Chemokines, CC / genetics
  • Chemokines, CC / immunology
  • Eosinophils / drug effects
  • Eosinophils / immunology*
  • Eosinophils / pathology
  • Fibroblasts / drug effects
  • Fibroblasts / immunology*
  • Fibroblasts / pathology
  • Fibrosis
  • Gene Expression
  • Gene Expression Profiling
  • Humans
  • Immunity, Innate
  • Interleukin-2 / immunology
  • Interleukin-2 / pharmacology
  • Interleukin-33 / immunology
  • Interleukin-33 / pharmacology
  • Interleukin-5 / genetics
  • Interleukin-5 / immunology*
  • Intestines / drug effects
  • Intestines / immunology
  • Intestines / pathology
  • Lung / drug effects
  • Lung / immunology
  • Lung / pathology
  • Lymphocytes / drug effects
  • Lymphocytes / immunology*
  • Lymphocytes / pathology
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / immunology*
  • Mesenchymal Stem Cells / pathology
  • Mice
  • Mice, Inbred mdx
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / immunology
  • Muscle, Skeletal / pathology
  • Muscular Dystrophy, Duchenne / genetics
  • Muscular Dystrophy, Duchenne / immunology*
  • Muscular Dystrophy, Duchenne / pathology


  • Chemokines, CC
  • Il33 protein, mouse
  • Interleukin-2
  • Interleukin-33
  • Interleukin-5