Requirement of Inducible Nitric Oxide Synthase for Skeletal Muscle Regeneration after Acute Damage
Requirement of Inducible Nitric Oxide Synthase for Skeletal Muscle Regeneration after Acute Damage
复制标题
DOI：
10.4049/jimmunol.1202903
复制
发表时间：
2013-02-15
影响因子：
4.4
通讯作者：
Rovere-Querini, Patrizia
中科院分区：
文献类型：
--
作者：
Rigamonti, Elena;Touvier, Thierry;Rovere-Querini, Patrizia
成人骨骼肌再生是肌肉干细胞激活、增殖和融合的结果，如肌源性前体细胞。巨噬细胞持续存在于再生的骨骼肌中，并参与修复过程。在不同的巨噬细胞群和肌源性前体细胞之间的相互作用中所涉及的信号仅被部分识别。在这项研究中，我们展示了由经典激活的巨噬细胞表达的诱导型一氧化氮合酶(INOS)在骨骼肌愈合中的关键作用。我们发现，在无菌损伤后，iNOS表达是组织有效再生所必需的，因为受伤的iNOS(-/-)小鼠肌肉中的肌源性前体细胞无法增殖和分化。我们还发现iNOS调节炎症细胞募集：iNOS(-/-)动物受损的肌肉表达明显高水平的趋化因子，如MIP2、MCP1、MIP-1α和MCP1，并在损伤后表现为更多的中性粒细胞浸润性和随后时间点的巨噬细胞持续存在。最后，我们发现iNOS在损伤肌肉中的表达仅限于浸润性巨噬细胞。据我们所知，这些数据提供了第一个证据，表明iNOS通过渗透的巨噬细胞表达有助于肌肉再生，揭示了一种新的炎症依赖性肌肉愈合机制。免疫学杂志，2013,190：1767-1777。
Adult skeletal muscle regeneration results from activation, proliferation, and fusion of muscle stem cells, such as myogenic precursor cells. Macrophages are consistently present in regenerating skeletal muscles and participate into the repair process. The signals involved in the cross-talk between various macrophage populations and myogenic precursor cells have been only partially identified. In this study, we show a key role of inducible NO synthase (iNOS), expressed by classically activated macrophages in the healing of skeletal muscle. We found that, after sterile injury, iNOS expression is required for effective regeneration of the tissue, as myogenic precursor cells in the muscle of injured iNOS(-/-) mice fail to proliferate and differentiate. We also found that iNOS modulates inflammatory cell recruitment: damaged muscles of iNOS(-/-) animals express significantly higher levels of chemokines such as MIP2, MCP1, MIP-1 alpha, and MCP1, and display more infiltrating neutrophils after injury and a persistence of macrophages at later time points. Finally, we found that iNOS expression in the injured muscle is restricted to infiltrating macrophages. To our knowledge, these data thus provide the first evidence that iNOS expression by infiltrating macrophages contributes to muscle regeneration, revealing a novel mechanism of inflammation-dependent muscle healing. The Journal of Immunology, 2013, 190: 1767-1777.