A Stromal Progenitor and ILC2 Niche Promotes Muscle Eosinophilia and Fibrosis-associated Gene Expression

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2021 Apr 14

PMID 33852849

Citations 23

Authors

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

Soon will be listed here.

Abstract

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.

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