Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy
Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy
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DOI：
10.1093/hmg/ddn376
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发表时间：
2009-02-01
影响因子：
3.5
通讯作者：
Tidball, James G.
中科院分区：
文献类型：
--
作者：
Villalta, S. Armando;Nguyen, Hal X.;Tidball, James G.
杜氏肌营养不良症（DMD）是最常见的，致命的，肌肉萎缩性疾病的儿童。先前的研究表明，肌肉巨噬细胞可能在促进DMD mdx小鼠模型的病理学中起重要作用。在本研究中，我们研究了巨噬细胞促进mdx营养不良的机制，并评估了巨噬细胞的表型是否在峰值肌肉坏死（4周龄）和肌肉再生（12周龄）阶段之间发生变化。我们发现，4周龄的mdx肌肉含有一群促炎的，经典激活的M1巨噬细胞，在体外通过NO介导的机制溶解肌肉。mdx小鼠中iNOS基因的基因切除也显著降低了4周龄mdx小鼠体内的肌膜溶解。然而，4周的mdx肌肉也含有一群交替激活的M2 a巨噬细胞，表达β-内酰胺酶。体外试验表明，M2 a巨噬细胞通过M2 a细胞中的精氨酸酶与M1细胞中的iNOS竞争其共同的酶底物精氨酸来减少M1巨噬细胞对肌细胞的溶解。在从mdx病理学急性高峰向再生阶段过渡期间，IL-4和IL-10的表达增加，其中任一种都可以使M1表型失活并促进可以增加组织修复的CD 163+、M2 c表型的活化。我们的研究结果进一步表明，IL-10刺激巨噬细胞激活其促进卫星细胞增殖的能力。M1表型的失活也与iNOS、IL-6、MCP-1和IP-10的表达减少有关。因此，这些结果表明，不同的巨噬细胞亚群可以促进肌营养不良症中的肌肉损伤或修复，并且影响M1和M2巨噬细胞群体之间平衡的治疗干预可能会影响肌营养不良症的病程。
Duchenne muscular dystrophy (DMD) is the most common, lethal, muscle-wasting disease of childhood. Previous investigations have shown that muscle macrophages may play an important role in promoting the pathology in the mdx mouse model of DMD. In the present study, we investigate the mechanism through which macrophages promote mdx dystrophy and assess whether the phenotype of the macrophages changes between the stage of peak muscle necrosis (4 weeks of age) and muscle regeneration (12 weeks). We find that 4-week-old mdx muscles contain a population of pro-inflammatory, classically activated M1 macrophages that lyse muscle in vitro by NO-mediated mechanisms. Genetic ablation of the iNOS gene in mdx mice also significantly reduces muscle membrane lysis in 4-week-old mdx mice in vivo. However, 4-week mdx muscles also contain a population of alternatively activated, M2a macrophages that express arginase. In vitro assays show that M2a macrophages reduce lysis of muscle cells by M1 macrophages through the competition of arginase in M2a cells with iNOS in M1 cells for their common, enzymatic substrate, arginine. During the transition from the acute peak of mdx pathology to the regenerative stage, expression of IL-4 and IL-10 increases, either of which can deactivate the M1 phenotype and promote activation of a CD163+, M2c phenotype that can increase tissue repair. Our findings further show that IL-10 stimulation of macrophages activates their ability to promote satellite cell proliferation. Deactivation of the M1 phenotype is also associated with a reduced expression of iNOS, IL-6, MCP-1 and IP-10. Thus, these results show that distinct subpopulations of macrophages can promote muscle injury or repair in muscular dystrophy, and that therapeutic interventions that affect the balance between M1 and M2 macrophage populations may influence the course of muscular dystrophy.