神经损伤诱发IgG免疫复合物激活痛觉神经元FcγRI参与神经病理性疼痛的机制研究

Neuropathic pain (NP) often accompanies by nerve injury, but the mechanisms of nerve injury induced-immune disorders in occurrence and development of NP remain unclear. Recent studies suggested that peripheral nerve injury caused the dorsal root nerve fiber demyelination that induced the body produce autoantibodies. Our previous studies demonstrated that the high-affinity activated receptor of IgG Fc segment (FcγRI) was expressed in nociceptive neurons of DRG, and the IgG-immune complex (IgG-IC) could activate some nociceptive neurons of DRG. We hypothesis that IgG-IC which was formed though self-antigens exposed by nerve injury bind with autoantibody may directly activate peripheral nociceptive neurons. In the propose project, we will elucidate this mechanism in the NP induced by nerve injury from three aspects. 1) We will study the expression changes of FcγRI and its downstream signals in nociceptive neurons of DRG in CCI rat model (NP model) and the vitroresponses of acute dissociated rat nociceptive neurons to IgG-IC. 2)Using the DRG neuronal FcγRI conditional knockout rats, the effect of FcγRI on pain and peripheral sensitization in rats of NP will be investigated. 3) We will further study the mechanisms of regulating FcγRI expression of nociceptive neurons in rats of CCI model. This study will clarify the mechanisms of IgG-IC involvement in the pathogenesis and development of NP by activating neuronal FcγRI, and provide potential targets for treatment of NP.

神经病理性疼痛（NP）常发生于神经损伤，但神经损伤诱发免疫失调参与NP发生发展的机理，目前尚不清楚。有研究发现外周神经损伤后背根纤维脱髓鞘，诱发机体产生自身抗体。前期发现在DRG痛觉神经元上表达FcγRI，且IgG 免疫复合物（IgG-IC）能够激活部分离体的痛觉神经元。我们假设神经损伤暴露的自身抗原与抗体结合形成IgG-IC可能直接激活外周痛觉神经元引起疼痛。本项目将通过CCI模型从三个方面阐明这一机制在NP中的作用。1）研究CCI模型大鼠DRG痛觉神经元中FcγRI和下游信号表达变化以及痛觉神经元对IgG-IC的反应变化。2）应用DRG神经元FcγRI条件敲除大鼠，研究CCI术后痛觉神经元FcγRI对痛觉行为和外周致敏的影响。3）进一步研究CCI模型中调控痛觉神经元FcγRI表达的机制。本研究将阐明IgG-IC通过激活痛觉神经元参与NP的机制，为NP的治疗提供潜在的靶点。

神经病理性疼痛（NP）常发生于神经损伤，但神经损伤诱发免疫失调参与NP发生发展的机理，目前尚不清楚。有研究发现外周神经损伤后背根纤维脱髓鞘，诱发机体产生自身抗体。在本研究项目中，申请人发现大鼠背根神经节（DRG）外周痛觉神经元表达IgG Fc高亲和力激活型受体Fc-gamma I型受体（Fc-gamma receptor I, FcγRI），并在神经损伤神经病理性疼痛后表达上调，DRG痛觉神经元中FcγRI相关信号活化。进一步的研究发现神经损伤引起针对外周神经纤维自身抗原的IgG型自身抗体增多，同时外周神经损伤引起DRG痛觉神经元合成表达CRP蛋白（FcγRI的内源性激活配体）增多。同时发现CRP足底皮内注射可引起实验动物痛觉过敏（机械痛敏和热痛敏），并能加强IgG-IC引起的实验动物痛觉过敏。申请人进一步应用Cre/loxP系统，以Pirt基因为外源性Cre基因的启动子，构建了DRG中Pirt阳性感觉神经元条件敲除Fcgr1基因大鼠（CKO大鼠）。应用CKO大鼠建立神经损伤神经病理性疼痛大鼠模型后，发现DRG神经元FcγRI相关信号活化程度下调，同时CKO大鼠CCI手术引起的神经病理性疼痛得到缓解。进一步进行DRG原位正常IgG注射，发现可以有效缓解CCI手术引起的大鼠神经病理性疼痛。这些结果提示我们，DRG痛觉神经元FcγRI相关信号参与神经损伤引起的神经病理性疼痛。DRG痛觉神经元FcγRI可能为治疗神经病理性疼痛的新靶点。