Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA; Institute for Immunology, University of California Irvine, Irvine, CA, USA.
Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA.
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.
尽管人们普遍认为慢性炎症会导致杜氏肌营养不良症（DMD）的发病机制，但嗜酸性粒细胞的功能和调节仍然是营养不良肌肉中 II 型先天免疫的一个不清楚的方面。我们报告了这样的观察结果，即 2 型固有淋巴细胞（ILC2）存在于骨骼肌中，并且是肌肉营养不良期间肌肉嗜酸性粒细胞的主要调节者。嗜酸性粒细胞在 DMD 患者和营养不良小鼠中升高，同时伴有白细胞介素（IL）-5，这是一种主要的嗜酸性粒细胞存活因子，主要由肌肉 ILC2 表达。我们还发现，IL-33 在营养不良的肌肉中上调，主要由成纤维细胞/脂肪生成祖细胞（FAP）产生。外源性 IL-33 和 IL-2 复合物（IL-2c）扩增了肌肉 ILC2 和嗜酸性粒细胞，减少了再生肌纤维的横截面积（CSA），并增加了与肌肉纤维化相关的基因表达。在营养不良的小鼠中删除 ILC2 可减轻肌肉嗜酸性粒细胞增多，并损害 IL-5 和纤维化相关基因的诱导。我们的研究结果强调了 FAP/ILC2/嗜酸性粒细胞轴促进 II 型先天免疫，这会影响肌肉营养不良期间再生和纤维化反应之间的平衡。
