Contreras-Shannon Verónica, Ochoa Oscar, Reyes-Reyna Sara M, Sun Dongxu, Michalek Joel E, Kuziel William A, McManus Linda M, Shireman Paula K
Univ. of Texas Health Science Center, 7703 Floyd Curl Dr., MC 7741, San Antonio, TX 78229-3900, USA.
Am J Physiol Cell Physiol. 2007 Feb;292(2):C953-67. doi: 10.1152/ajpcell.00154.2006. Epub 2006 Oct 4.
Chemokines recruit inflammatory cells to sites of injury, but the role of the CC chemokine receptor 2 (CCR2) during regenerative processes following ischemia is poorly understood. We studied injury, inflammation, perfusion, capillary formation, monocyte chemotactic protein-1 (MCP-1) levels, muscle regeneration, fat accumulation, and transcription factor activation in hindlimb muscles of CCR2-/- and wild-type (WT) mice following femoral artery excision (FAE). In both groups, muscle injury and restoration of vascular perfusion were similar. Nevertheless, edema and neutrophil accumulation were significantly elevated in CCR2-/- compared with WT mice at day 1 post-FAE and fewer macrophages were present at day 3. MCP-1 levels in post-ischemic calf muscle of CCR2-/- animals were significantly elevated over baseline through 14 days post-FAE and were higher than WT mice at days 1, 7, and 14. In addition, CCR2-/- mice exhibited impaired muscle regeneration, decreased muscle fiber size, and increased intermuscular adipocytes with similar capillaries/mm(2) postinjury. Finally, the transcription factors, MyoD and signal transducers of and activators of transcription-3 (STAT3), were significantly increased above baseline but did not differ significantly between groups at any time point post-FAE. These findings suggest that increases in MCP-1, and possibly, MyoD and STAT3, may modulate molecular signaling in CCR2-/- mice during inflammatory and regenerative events. Furthermore, alterations in neutrophil and macrophage recruitment in CCR2-/- mice may critically alter the normal progression of downstream regenerative events in injured skeletal muscle and may direct myogenic precursor cells in the regenerating milieu toward an adipogenic phenotype.
趋化因子将炎性细胞募集到损伤部位，但C-C趋化因子受体2（CCR2）在缺血后再生过程中的作用仍知之甚少。我们研究了股动脉切除（FAE）后CCR2基因敲除小鼠和野生型（WT）小鼠后肢肌肉中的损伤、炎症、灌注、毛细血管形成、单核细胞趋化蛋白-1（MCP-1）水平、肌肉再生、脂肪堆积以及转录因子激活情况。在两组中，肌肉损伤和血管灌注的恢复情况相似。然而，FAE后第1天，与WT小鼠相比，CCR2基因敲除小鼠的水肿和中性粒细胞聚集显著增加，而第3天巨噬细胞数量较少。CCR2基因敲除动物缺血后小腿肌肉中的MCP-1水平在FAE后14天内均显著高于基线水平，且在第1、7和14天高于WT小鼠。此外，CCR2基因敲除小鼠表现出肌肉再生受损、肌纤维尺寸减小以及肌间脂肪细胞增加，损伤后每平方毫米毛细血管数量相似。最后，转录因子MyoD和信号转导及转录激活因子3（STAT3）在基线水平之上显著增加，但在FAE后任何时间点两组之间均无显著差异。这些发现表明，MCP-1以及可能的MyoD和STAT3的增加可能在炎症和再生事件期间调节CCR2基因敲除小鼠中的分子信号传导。此外，CCR2基因敲除小鼠中性粒细胞和巨噬细胞募集的改变可能会严重改变受损骨骼肌下游再生事件的正常进程，并可能将再生环境中的生肌前体细胞导向脂肪生成表型。
