A stromal progenitor and ILC2 niche promotes muscle eosinophilia and fibrosis-associated gene expression
Jenna M. Kastenschmidt,
Gerald Coulis,
Philip K. Farahat,
Phillip Pham,
Rodolfo Rios,
Therese T. Cristal,
Ali H. Mannaa,
Rachel E. Ayer,
Rayan Yahia,
Archis A. Deshpande,
Brandon S. Hughes,
Adam K. Savage,
Carlee R. Giesige,
Scott Q. Harper,
Richard M. Locksley,
Tahseen Mozaffar,
S. Armando Villalta
Affiliations
Jenna M. Kastenschmidt
Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA; Institute for Immunology, University of California Irvine, Irvine, CA, USA
Gerald Coulis
Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA; Institute for Immunology, University of California Irvine, Irvine, CA, USA
Philip K. Farahat
Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA; Institute for Immunology, University of California Irvine, Irvine, CA, USA
Phillip Pham
Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA
Rodolfo Rios
Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA
Therese T. Cristal
Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA
Ali H. Mannaa
Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA
Rachel E. Ayer
Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA
Rayan Yahia
Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA
Archis A. Deshpande
Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA
Brandon S. Hughes
Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA
Adam K. Savage
Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA; Departments of Medicine and Microbiology & Immunology, University of California San Francisco, San Francisco, CA, USA
Carlee R. Giesige
Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA; Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
Scott Q. Harper
Biomedical Sciences Graduate Program, The Ohio State University, Columbus, OH, USA; Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University, Columbus, OH, USA
Richard M. Locksley
Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA
Tahseen Mozaffar
Institute for Immunology, University of California Irvine, Irvine, CA, USA; Department of Neurology, University of California Irvine, Irvine, CA, USA; Department of Orthopaedic Surgery, University of California Irvine, Irvine, CA, USA; Department of Pathology and Laboratory Medicine, University of California Irvine, Irvine, CA, USA
S. Armando Villalta
Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA; Institute for Immunology, University of California Irvine, Irvine, CA, USA; Department of Neurology, University of California Irvine, Irvine, CA, USA; Corresponding author
Summary: 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.
