A Stromal Progenitor and ILC2 Niche Promotes Eosinophilia in Skeletal Muscle

Chronic muscle inflammation contributes to the pathogenesis of Duchenne muscular dystrophy (DMD), a lethal muscle disorder attributed to dystrophin gene mutations. However, the function and regulation of eosinophilia, an unappreciated facet of type II innate immunity in dystrophic muscle, remain poorly understood. Here, we report the novel observation that group 2 innate lymphoid cells (ILC2s) are present in skeletal muscle and are the principal regulators of muscle eosinophilia during muscular dystrophy. Eosinophils were elevated in DMD patients and dystrophic mice, along with the major eosinophil survival factor, interleukin-5 (IL-5). ILC2s were present in healthy skeletal muscle, were activated and expanded in number during muscular dystrophy in mice, and were the sole source of IL-5. Muscle ILC2s were expanded by IL-33, which was upregulated in dystrophic muscle and was predominantly produced by fibro/adipogenic progenitor cells (FAPs). Exogenous IL-33 also promoted muscle eosinophilia, which was further augmented by combined treatment with IL-2 complex (IL-2c). The deletion of ILC2s in dystrophic mice prevented eosinophilia and mitigated the IL-33/IL-2c-mediated increase of muscle eosinophils and IL-5 expression. Our findings establish that interactions between FAPs and ILC2s regulate type II innate immunity in dystrophic muscle and promote muscle eosinophilia during muscular dystrophy.