Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype.
Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype.
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DOI：
10.1083/jcb.201510086
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发表时间：
2016-04-25
期刊：
影响因子：
--
通讯作者：
Spencer MJ
中科院分区：
文献类型：
--
作者：
Capote J;Kramerova I;Martinez L;Vetrone S;Barton ER;Sweeney HL;Miceli MC;Spencer MJ
在杜氏肌营养不良模型中，免疫调节剂骨桥蛋白的消除与纤维化的减少和肌肉强度的改善相关。在这里，卡波特等人。研究表明，骨桥蛋白消融使营养不良的巨噬细胞偏向于促再生表型，从而在长期功能测试中改善和维持肌肉质量和力量。在退行性疾病杜氏肌营养不良症中，炎症细胞进入肌肉以应对重复的肌肉损伤。肌肉再生需要免疫因子，但慢性炎症会产生促纤维化环境，从而加剧疾病进展。骨桥蛋白 (OPN) 是一种在营养不良的肌肉中高度表达的免疫调节剂。 OPN 的消融与纤维化的减少、肌肉力量的改善以及自然杀伤 T (NKT) 细胞计数的减少相关。在这里，我们证明 OPN 消融观察到的营养不良表型的改善并不是由于 NKT 细胞的减少所致。 OPN 消融通过减少 M1 和 M2a 并增加 M2c 子集，使巨噬细胞极化偏向促再生表型。这些变化与促再生因子胰岛素样生长因子 1、白血病抑制因子和尿激酶型纤溶酶原激活剂的表达增加有关。此外，巨噬细胞极化的改变与肌肉重量和肌纤维直径的增加相关，从而导致 mdx 小鼠肌肉力量和功能的长期改善。这些发现表明 OPN 消融通过巨噬细胞分泌促肌生长因子来促进肌肉修复。
Ablation of the immunomodulator osteopontin correlates with reduced fibrosis and improved muscle strength in Duchenne muscular dystrophy models. Here, Capote et al. show that osteopontin ablation skews dystrophic macrophages toward a pro-regenerative phenotype, leading to improved and sustained muscle mass and strength in long-term functional testing. In the degenerative disease Duchenne muscular dystrophy, inflammatory cells enter muscles in response to repetitive muscle damage. Immune factors are required for muscle regeneration, but chronic inflammation creates a profibrotic milieu that exacerbates disease progression. Osteopontin (OPN) is an immunomodulator highly expressed in dystrophic muscles. Ablation of OPN correlates with reduced fibrosis and improved muscle strength as well as reduced natural killer T (NKT) cell counts. Here, we demonstrate that the improved dystrophic phenotype observed with OPN ablation does not result from reductions in NKT cells. OPN ablation skews macrophage polarization toward a pro-regenerative phenotype by reducing M1 and M2a and increasing M2c subsets. These changes are associated with increased expression of pro-regenerative factors insulin-like growth factor 1, leukemia inhibitory factor, and urokinase-type plasminogen activator. Furthermore, altered macrophage polarization correlated with increases in muscle weight and muscle fiber diameter, resulting in long-term improvements in muscle strength and function in mdx mice. These findings suggest that OPN ablation promotes muscle repair via macrophage secretion of pro-myogenic growth factors.
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