An anti-inflammatory role for leukemia inhibitory factor receptor signaling in regenerating skeletal muscle
An anti-inflammatory role for leukemia inhibitory factor receptor signaling in regenerating skeletal muscle
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DOI：
10.1007/s00418-012-1018-0
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发表时间：
2013-01-01
影响因子：
2.3
通讯作者：
White, Jason D.
中科院分区：
文献类型：
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作者：
Hunt, Liam C.;Upadhyay, Aradhana;White, Jason D.
病理学和损伤后的骨骼肌再生需要炎症细胞和生肌细胞的协调作用，分别去除受损组织和重建合胞肌细胞。肌肉挫伤后，细胞因子白血病抑制因子 (LIF) 上调，Lif 敲除会对肌肉再生的形态参数产生负面影响。尽管推测 LIF 通过直接影响生肌细胞来调节肌肉再生，但 LIF 在骨骼肌再生中的炎症作用尚未得到研究。因此，在小鼠notexin诱导的肌肉再生的特定炎症和生肌阶段，使用拮抗剂MH35-BD检查了LIF的表达和功能。将notexin肌内注射到胫骨前肌后，LIF蛋白和mRNA在两个不同的阶段上调。 LIF 上调的第一阶段与促炎细胞因子表达增加同时发生；第二阶段与肌原性分化和新肌管形成同时发生。在 LIF 上调的第二阶段施用 LIF 受体拮抗剂 MH35-BD 对肌原性分化或与炎症相关的基因的转录表达没有显着影响；再生肌肉的形态参数没有显着差异。相反，当在急性炎症阶段施用 MH35-BD 时，观察到促炎细胞因子 Tnf（肿瘤坏死因子）、Il1b（白细胞介素 1β）和 Il6（白细胞介素 6）的基因转录增加，同时浸润肌肉的 Ly6G 阳性中性粒细胞数量增加。随后，与假手术相比，MH35-BD 治疗组中肌原分化所需的 Myog (肌细胞生成素) mRNA 减少，随后形成的肌管数量显着减少。因此，在骨骼肌再生的炎症阶段，LIF 受体的拮抗作用似乎会诱导炎症反应，从而抑制随后的肌管形成。我们认为 LIF 在骨骼肌再生中的主要作用似乎是调节炎症反应，而不是直接影响生肌细胞。
Skeletal muscle regeneration in pathology and following injury requires the coordinated actions of inflammatory cells and myogenic cells to remove damaged tissue and rebuild syncytial muscle cells, respectively. Following contusion injury to muscle, the cytokine leukemia inhibitor factor (LIF) is up-regulated and knockout of Lif negatively impacts on morphometric parameters of muscle regeneration. Although it was speculated that LIF regulates muscle regeneration through direct effects on myogenic cells, the inflammatory effects of LIF have not been examined in regenerating skeletal muscle. Therefore, the expression and function of LIF was examined using the antagonist MH35-BD during specific inflammatory and myogenic stages of notexin-induced muscle regeneration in mice. LIF protein and mRNA were up-regulated in two distinct phases following intramuscular injection of notexin into tibialis anterior muscles. The first phase of LIF up-regulation coincided with the increased expression of pro-inflammatory cytokines; the second phase coincided with myogenic differentiation and formation of new myotubes. Administration of the LIF receptor antagonist MH35-BD during the second phase of LIF up-regulation had no significant effects on transcript expression of genes required for myogenic differentiation or associated with inflammation; there were no significant differences in morphometric parameters of the regenerating muscle. Conversely, when MH35-BD was administered during the acute inflammatory phase, increased gene transcripts for the pro-inflammatory cytokines Tnf (Tumor necrosis factor), Il1b (Interleukin-1 beta) and Il6 (Interleukin-6) alongside an increase in the number of Ly6G positive neutrophils infiltrating the muscle were observed. This was followed by a reduction in Myog (Myogenin) mRNA, which is required for myogenic differentiation, and the subsequent number of myotubes formed was significantly decreased in MH35-BD-treated groups compared to sham. Thus, antagonism of the LIF receptor during the inflammatory phase of skeletal muscle regeneration appeared to induce an inflammatory response that inhibited subsequent myotube formation. We propose that the predominant role of LIF in skeletal muscle regeneration appears to be in regulating the inflammatory response rather than directly effecting myogenic cells.