Mechanistic insights into the role of the chemokine CCL2/CCR2 axis in dorsal root ganglia to peripheral inflammation and pain hypersensitivity.
Mechanistic insights into the role of the chemokine CCL2/CCR2 axis in dorsal root ganglia to peripheral inflammation and pain hypersensitivity.
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DOI：
10.1186/s12974-021-02125-y
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发表时间：
2021-03-23
影响因子：
9.3
通讯作者：
Sarret P
中科院分区：
文献类型：
--
作者：
Dansereau MA;Midavaine É;Bégin-Lavallée V;Belkouch M;Beaudet N;Longpré JM;Mélik-Parsadaniantz S;Sarret P
据报道，疼痛是常见形式的炎性关节炎疾病致残的主要原因。趋化因子CCL 2/CCR 2轴作为伤害性处理、神经炎症和神经元-胶质细胞通讯的关键参与者，在控制慢性疼痛性关节炎方面具有巨大的前景。在这里，我们研究了背根神经节（DRG）中的CCL 2/CCR 2系统如何参与外周炎性疼痛敏化。重复鞘内（i.t.）在补充性福尔马林和完全弗氏佐剂（CFA）炎性模型中，测试施用CCR 2拮抗剂INCB 3344逆转伤害感受性相关行为的能力。我们进一步通过qPCR测定CFA处理的大鼠DRG神经元中CCL 2/CCR 2、SP和CGRP的表达。使用DRG外植体，急性分离的初级感觉神经元和钙动员测定，我们还评估了CCL 2的释放和伤害感受器的致敏作用。最后，我们研究了免疫组织化学神经结扎后的轴突运输的CCL 2，SP和CGRP从CFA治疗的大鼠坐骨神经。我们首先发现CFA诱导的足水肿引起同侧DRG中CCL 2/CCR 2和SP表达的增加，其在INCB 3344处理后降低。在CFA后第3天和第10天，这种原伤害感受性神经调节剂的上调伴随着伤害感受性神经元兴奋性的增强，如CCL 2刺激后细胞内钙动员的CCR 2依赖性增加所揭示的。在DRG外植体中，我们进一步证明了外周炎症后CCL 2的释放增加。最后，外周炎症后伤害感受器的兴奋刺激SP在其周围神经末梢的顺行运输。重要的是，阻断CCR 2通过限制钙动员降低感觉神经元的兴奋性，随后降低SP向外周的外周转运。最后，CCR 2的药理学抑制逆转了接受福尔马林注射的大鼠中CCL 2的前伤害性作用，并显著减少了CFA处理的大鼠中的神经源性炎症以及刺激诱发和运动诱发的伤害性行为。我们的研究结果提供了重要的机制的见解，CCL 2/CCR 2在DRG的外周炎症，伤害感受器敏化，疼痛超敏反应的发展中的作用。我们进一步揭示了靶向CCR 2治疗疼痛性炎症性疾病的治疗潜力。
Pain is reported as the leading cause of disability in the common forms of inflammatory arthritis conditions. Acting as a key player in nociceptive processing, neuroinflammation, and neuron-glia communication, the chemokine CCL2/CCR2 axis holds great promise for controlling chronic painful arthritis. Here, we investigated how the CCL2/CCR2 system in the dorsal root ganglion (DRG) contributes to the peripheral inflammatory pain sensitization. Repeated intrathecal (i.t.) administration of the CCR2 antagonist, INCB3344 was tested for its ability to reverse the nociceptive-related behaviors in the tonic formalin and complete Freund’s adjuvant (CFA) inflammatory models. We further determined by qPCR the expression of CCL2/CCR2, SP and CGRP in DRG neurons from CFA-treated rats. Using DRG explants, acutely dissociated primary sensory neurons and calcium mobilization assay, we also assessed the release of CCL2 and sensitization of nociceptors. Finally, we examined by immunohistochemistry following nerve ligation the axonal transport of CCL2, SP, and CGRP from the sciatic nerve of CFA-treated rats. We first found that CFA-induced paw edema provoked an increase in CCL2/CCR2 and SP expression in ipsilateral DRGs, which was decreased after INCB3344 treatment. This upregulation in pronociceptive neuromodulators was accompanied by an enhanced nociceptive neuron excitability on days 3 and 10 post-CFA, as revealed by the CCR2-dependent increase in intracellular calcium mobilization following CCL2 stimulation. In DRG explants, we further demonstrated that the release of CCL2 was increased following peripheral inflammation. Finally, the excitation of nociceptors following peripheral inflammation stimulated the anterograde transport of SP at their peripheral nerve terminals. Importantly, blockade of CCR2 reduced sensory neuron excitability by limiting the calcium mobilization and subsequently decreased peripheral transport of SP towards the periphery. Finally, pharmacological inhibition of CCR2 reversed the pronociceptive action of CCL2 in rats receiving formalin injection and significantly reduced the neurogenic inflammation as well as the stimuli-evoked and movement-evoked nociceptive behaviors in CFA-treated rats. Our results provide significant mechanistic insights into the role of CCL2/CCR2 within the DRG in the development of peripheral inflammation, nociceptor sensitization, and pain hypersensitivity. We further unveil the therapeutic potential of targeting CCR2 for the treatment of painful inflammatory disorders.
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影响因子：
15.3
作者：
Gong, JH;Ratkay, LG;Waterfield, JD;ClarkLewis, I
通讯作者：
ClarkLewis, I
影响因子：
3.3
作者：
Bhangoo SK;Ripsch MS;Buchanan DJ;Miller RJ;White FA
通讯作者：
White FA
影响因子：
4.4
作者：
Brodmerkel, CM;Huber, R;Vaddi, K
通讯作者：
Vaddi, K
影响因子：
3.8
作者：
Ahn, DK;Lee, KR;Park, JS
通讯作者：
Park, JS
影响因子：
5.3
作者：
Belkouch, Mounir;Dansereau, Marc-Andre;Sarret, Philippe
通讯作者：
Sarret, Philippe