Franco-Enzástiga Úrzula, Natarajan Keerthana, David Eric T, Patel Krish J, Ravirala Abhira, Price Theodore J
Center for Advanced Pain Studies, School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas 75080.
bioRxiv. 2023 Jun 5:2023.06.03.543579. doi: 10.1101/2023.06.03.543579.
Type I interferons (IFNs) increase the excitability of dorsal root ganglion (DRG) neurons via activation of MNK-eIF4E translation signaling to promote pain sensitization in mice. Activation of STING signaling is a key component of type I IFN induction. Manipulation of STING signaling is an active area of investigation in cancer and other therapeutic areas. Vinorelbine is a chemotherapeutic that activates STING and has been shown to cause pain and neuropathy in oncology clinical trials in patients. There are conflicting reports on whether STING signaling promotes or inhibits pain in mice. We hypothesized that vinorelbine would cause a neuropathic pain-like state in mice via STING and signaling pathways in DRG neurons associated with type I IFN induction. Vinorelbine (10 mg/kg, i.v.) induced tactile allodynia and grimacing in WT male and female mice and increased p-IRF3 and type I IFN protein in peripheral nerves. In support of our hypothesis, vinorelbine-mediated pain was absent in male and female Sting mice. Vinorelbine also failed to induce IRF3 and type I IFN signaling in these mice. Since type I IFNs engage translational control via MNK1-eIF4E in DRG nociceptors, we assessed vinorelbine-mediated p-eIF4E changes. Vinorelbine increased p-eIF4E in DRG in WT animals but not in Sting or (MNK1 KO) mice. Consistent with these biochemical findings, vinorelbine had an attenuated pro-nociceptive effect in male and female MNK1 KO mice. Our findings support the conclusion that activation of STING signaling in the peripheral nervous system causes a neuropathic pain-like state that is mediated by type I IFN signaling to DRG nociceptors.
I型干扰素（IFN）通过激活MNK-eIF4E翻译信号通路增加背根神经节（DRG）神经元的兴奋性，从而促进小鼠的疼痛敏化。STING信号通路的激活是I型干扰素诱导的关键组成部分。STING信号通路的调控是癌症和其他治疗领域的一个活跃研究领域。长春瑞滨是一种激活STING的化疗药物，在肿瘤学临床试验中已被证明会导致患者疼痛和神经病变。关于STING信号通路在小鼠中是促进还是抑制疼痛，存在相互矛盾的报道。我们假设长春瑞滨会通过STING以及与I型干扰素诱导相关的DRG神经元信号通路，在小鼠中引起类似神经性疼痛的状态。长春瑞滨（10 mg/kg，静脉注射）在野生型雄性和雌性小鼠中诱发触觉异常性疼痛和面部 grimacing，并增加外周神经中p-IRF3和I型干扰素蛋白。支持我们的假设的是，雄性和雌性Sting小鼠不存在长春瑞滨介导的疼痛。长春瑞滨在这些小鼠中也未能诱导IRF3和I型干扰素信号通路。由于I型干扰素通过MNK1-eIF4E在DRG伤害感受器中参与翻译控制，我们评估了长春瑞滨介导的p-eIF4E变化。长春瑞滨在野生型动物的DRG中增加了p-eIF4E，但在Sting或MNK1基因敲除（MNK1 KO）小鼠中没有增加。与这些生化结果一致，长春瑞滨在雄性和雌性MNK1 KO小鼠中的促伤害感受作用减弱。我们的研究结果支持以下结论：外周神经系统中STING信号通路的激活会导致一种由I型干扰素信号传导至DRG伤害感受器介导的类似神经性疼痛的状态。
