Wound healing is impaired in MyD88-Deficient mice -: A role for MyD88 in the regulation of wound healing by adenosine A2A receptors
Wound healing is impaired in MyD88-Deficient mice -: A role for MyD88 in the regulation of wound healing by adenosine A2A receptors
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DOI：
10.2353/ajpath.2007.061048
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发表时间：
2007-12-01
影响因子：
6
通讯作者：
Leibovich, Samuel Joseph
中科院分区：
文献类型：
--
作者：
Macedo, Lisa;Pinhal-Enfield, Grace;Leibovich, Samuel Joseph
toll样受体（TLR）与腺苷A（2A）受体（A(2A)R）信号传导开关的协同作用从炎性细胞因子如肿瘤坏死因子-a的产生到血管生成生长因子血管内皮生长因子（VEGF）的产生。我们在这项研究中表明，这种开关非常需要通过MyD88、IRAK4和TRAF6发出信号。缺乏MyD88（MyD88(-/-)）或IRAK4（IRAK4(-/-)）的小鼠巨噬细胞对TLR激动剂缺乏反应性，对A(2A)R激动剂无反应；通过表达VEGF。用siRNA抑制RAW264.7巨噬细胞中TRAF6的表达也阻断了它们对TLR和A(2A)R激动剂的反应。MyD88（-/-）小鼠的皮肤切口愈合速度明显慢于野生型MyD88（+/+）小鼠，表现为收缩延迟，肉芽组织形成减少和延迟，新血管密度降低。尽管MyD88（-/-）伤口中巨噬细胞的积累水平高于对照组，但MyD88（+/+）伤口中VEGF和hif1 - α mrna的表达升高。A(2A)R激动剂CGS21680促进MyD88（+/+）创面修复，刺激血管生成，但对MyD88（-/-）创面愈合无显著影响。这些结果表明，在体外观察到的TLR和A(2A)R信号之间的协同相互作用，将巨噬细胞从炎症表型转换为血管生成表型，也在体内伤口愈合中发挥作用。
Synergy between Toll-like receptor (TLR) and adenosine A(2A) receptor (A(2A)R) signaling switches macrophages; from production of inflammatory cytokines such as tumor necrosis factor-a to production of the angiogenic growth factor vascular endothelial growth factor (VEGF). We show in this study that this switch critically requires signaling through MyD88, IRAK4, and TRAF6. Macrophages from mice lacking MyD88 (MyD88(-/-)) or IRAK4 (IRAK4(-/-)) lacked responsiveness to TLR agonists and did not respond to A(2A)R agonists; by expressing VEGF. Suppression of TRAF6 expression with siRNA in RAW264.7 macrophages also blocked their response to TLR and A(2A)R agonists. Excisional skin wounds in MyD88(-/-) mice healed at a markedly slower rate than wounds in wild-type MyD88(+/+) mice, showing delayed contraction, decreased and delayed granulation tissue formation, and reduced new blood vessel density. Although macrophages accumulated to higher levels in MyD88(-/-) wounds than in controls, expression of VEGF and HIF1-alpha mRNAs was elevated in MyD88(+/+) wounds. CGS21680, an A(2A)R agonist, promoted repair in MyD88(+/+) wounds and stimulated angiogenesis but had no significant effect on healing of MyD88(-/-) wounds. These results suggest that the synergistic interaction between TLR and A(2A)R signaling observed in vitro that switches macrophages from an inflammatory to an angiogenic phenotype also plays a role in wound healing in vivo.