Mechanisms underlying mechanical sensitization induced by complement C5a: the roles of macrophages, TRPV1, and calcitonin gene-related peptide receptors
Mechanisms underlying mechanical sensitization induced by complement C5a: the roles of macrophages, TRPV1, and calcitonin gene-related peptide receptors
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DOI：
10.1097/j.pain.0000000000001449
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发表时间：
2018-11
期刊：
影响因子：
7.4
通讯作者：
Charles A. Warwick;L. Shutov;A. Shepherd;D. Mohapatra;Y. Usachev
中科院分区：
文献类型：
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作者：
Charles A. Warwick;L. Shutov;A. Shepherd;D. Mohapatra;Y. Usachev
摘要补体系统在炎症性和神经性疼痛的发生发展中起着重要作用，但其机制尚不清楚。最近，我们确定了负责补体系统成分C5 a诱导的热过敏性的信号通路。在这里，我们研究C5 a的另一个重要作用的机制，机械超敏反应的诱导。我们发现足底注射C5 a会产生剂量依赖性的机械致敏作用，并且这种作用可以通过雄性和雌性小鼠巨噬细胞的化学发生消融来阻断。敲除TRPV 1或用TRPV 1拮抗剂AMG 9810或5′-碘树脂毒素（5′-IRTX）预处理可显著降低C5 a诱导的机械致敏作用。值得注意的是，C5 a注射后90分钟局部给予5′-IRTX导致机械致敏性缓慢但完全逆转，表明TRPV 1活性是维持C5 a诱导的机械超敏性所必需的。这种缓慢的逆转表明可能涉及神经源性炎症和神经肽释放。事实上，用降钙素基因相关肽（CGRP）受体拮抗剂（但不是神经激肽1受体拮抗剂）预处理可防止C5 a诱导的机械致敏。此外，足底注射CGRP在野生型和TRPV 1基因敲除小鼠中产生显著的机械致敏作用。总之，这些发现表明，C5 a通过启动巨噬细胞到感觉神经元的信号级联产生机械致敏，该信号级联涉及TRPV 1和CGRP受体的激活作为该过程中的关键步骤。
Abstract The complement system significantly contributes to the development of inflammatory and neuropathic pain, but the underlying mechanisms are poorly understood. Recently, we identified the signaling pathway responsible for thermal hypersensitivity induced by the complement system component C5a. Here, we examine the mechanisms of another important action of C5a, induction of mechanical hypersensitivity. We found that intraplantar injection of C5a produced a dose-dependent mechanical sensitization and that this effect was blocked by chemogenetic ablation of macrophages in both male and female mice. Knockout of TRPV1 or pretreatment with the TRPV1 antagonists, AMG9810 or 5′-iodoresiniferatoxin (5′-IRTX), significantly reduced C5a-induced mechanical sensitization. Notably, local administration of 5′-IRTX 90 minutes after C5a injection resulted in a slow, but complete, reversal of mechanical sensitization, indicating that TRPV1 activity was required for maintaining C5a-induced mechanical hypersensitivity. This slow reversal suggests that neurogenic inflammation and neuropeptide release may be involved. Indeed, pretreatment with a calcitonin gene-related peptide (CGRP) receptor antagonist (but not an antagonist of the neurokinin 1 receptor) prevented C5a-induced mechanical sensitization. Furthermore, intraplantar injection of CGRP produced significant mechanical sensitization in both wild-type and TRPV1 knockout mice. Taken together, these findings suggest that C5a produces mechanical sensitization by initiating macrophage-to-sensory-neuron signaling cascade that involves activation of TRPV1 and CGRP receptor as critical steps in this process.