Mojumdar Kamalika, Giordano Christian, Lemaire Christian, Liang Feng, Divangahi Maziar, Qureshi Salman T, Petrof Basil J
Meakins-Christie Laboratories and Program for Translational Research in Respiratory Diseases, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
J Pathol. 2016 May;239(1):10-22. doi: 10.1002/path.4689. Epub 2016 Mar 16.
Injury to skeletal muscle, whether acute or chronic, triggers macrophage-mediated innate immunity in a manner which can be either beneficial or harmful for subsequent repair. Endogenous ligands for Toll-like receptor 2 (TLR2) are released by damaged tissues and might play an important role in activating the innate immune system following muscle injury. To test this hypothesis, we compared macrophage behaviour and muscle repair mechanisms in mice lacking TLR2 under conditions of either acute (cardiotoxin-induced) or chronic (mdx mouse genetic model of Duchenne muscular dystrophy; DMD) muscle damage. In previously healthy muscle subjected to acute damage, TLR2 deficiency reduced macrophage numbers in the muscle post-injury but did not alter the expression pattern of the prototypical macrophage polarization markers iNOS and CD206. In addition, there was abnormal persistence of necrotic fibres and impaired regeneration in TLR2-/- muscles after acute injury. In contrast, TLR2 ablation in chronically diseased muscles of mdx mice not only resulted in significantly reduced macrophage numbers but additionally modified their phenotype by shifting from inflammatory (iNOS(pos) CD206(neg) ) to more anti-inflammatory (iNOS(neg) CD206(pos) ) characteristics. This decrease in macrophage-mediated inflammation was associated with ameliorated muscle histopathology and improved force-generating capacity of the dystrophic muscle. Our results suggest that the role of TLR2 in macrophage function and skeletal muscle repair depends greatly upon the muscle injury context, and raise the possibility that inhibition of TLR2 could serve as a useful therapeutic measure in DMD.
骨骼肌损伤，无论是急性还是慢性，都会以一种对后续修复可能有益或有害的方式触发巨噬细胞介导的先天性免疫。Toll样受体2（TLR2）的内源性配体由受损组织释放，可能在肌肉损伤后激活先天性免疫系统中发挥重要作用。为了验证这一假设，我们比较了在急性（心脏毒素诱导）或慢性（杜氏肌营养不良症（DMD）的mdx小鼠遗传模型）肌肉损伤条件下缺乏TLR2的小鼠的巨噬细胞行为和肌肉修复机制。在先前健康的肌肉遭受急性损伤后，TLR2缺陷减少了损伤后肌肉中的巨噬细胞数量，但没有改变典型巨噬细胞极化标志物iNOS和CD206的表达模式。此外，急性损伤后，TLR2 - / - 肌肉中坏死纤维持续异常，再生受损。相比之下，在mdx小鼠的慢性患病肌肉中敲除TLR2不仅导致巨噬细胞数量显著减少，还通过从炎症性（iNOS阳性CD206阴性）转变为更具抗炎性（iNOS阴性CD206阳性）特征来改变其表型。巨噬细胞介导的炎症减少与改善的肌肉组织病理学和营养不良肌肉的力产生能力提高有关。我们的结果表明，TLR2在巨噬细胞功能和骨骼肌修复中的作用在很大程度上取决于肌肉损伤的背景，并提出抑制TLR2可能作为DMD的一种有用治疗措施的可能性。
