Fan Churmy Y, McAllister Brendan B, Stokes-Heck Sierra, Harding Erika K, Pereira de Vasconcelos Aliny, Mah Laura K, Lima Lucas V, van den Hoogen Nynke J, Rosen Sarah F, Ham Boram, Zhang Zizhen, Liu Hongrui, Zemp Franz J, Burkhard Regula, Geuking Markus B, Mahoney Douglas J, Zamponi Gerald W, Mogil Jeffrey S, Ousman Shalina S, Trang Tuan
Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada; Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.
Faculty of Veterinary Medicine, University of Calgary, Calgary, Canada; Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada; Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.
Neuron. 2025 Mar 19;113(6):896-911.e9. doi: 10.1016/j.neuron.2025.01.005. Epub 2025 Jan 31.
Chronic pain is a leading cause of disability, affecting more women than men. Different immune cells contribute to this sexual divergence, but the mechanisms, especially in females, are not well defined. We show that pannexin-1 (Panx1) channels on microglia and T cells differentially cause mechanical allodynia, a debilitating symptom of neuropathic pain. In male rodents, Panx1 drives vascular endothelial growth factor-A (VEGF-A) release from microglia. Cell-specific knockdown of microglial Panx1 or pharmacological blockade of the VEGF receptor attenuated allodynia in nerve-injured males. In females, nerve injury increased spinal CD8 T cells and leptin levels. Leptin release from female-derived CD8 T cells was Panx1 dependent, and intrathecal leptin-neutralizing antibody injection sex-specifically reversed allodynia. Adoptive transfer of female-derived CD8 T cells caused robust allodynia, which was prevented by a leptin-neutralizing antibody or leptin small interfering RNA (siRNA) knockdown. Panx1-targeted approaches may alleviate neuropathic pain in both sexes, while T cell- and leptin-directed treatments could have sex-dependent benefits for women.
慢性疼痛是导致残疾的主要原因，女性受影响的人数多于男性。不同的免疫细胞导致了这种性别差异，但其中的机制，尤其是在女性中的机制，尚未明确。我们发现，小胶质细胞和T细胞上的泛连接蛋白-1（Panx1）通道分别导致机械性异常性疼痛，这是神经性疼痛的一种使人衰弱的症状。在雄性啮齿动物中，Panx1促使小胶质细胞释放血管内皮生长因子-A（VEGF-A）。小胶质细胞Panx1的细胞特异性敲低或VEGF受体的药物阻断可减轻神经损伤雄性动物的异常性疼痛。在雌性动物中，神经损伤会增加脊髓CD8 T细胞和瘦素水平。雌性来源的CD8 T细胞释放瘦素依赖于Panx1，鞘内注射瘦素中和抗体可特异性逆转雌性动物的异常性疼痛。过继转移雌性来源的CD8 T细胞会导致强烈的异常性疼痛，而瘦素中和抗体或瘦素小干扰RNA（siRNA）敲低可预防这种疼痛。靶向Panx1的方法可能会减轻两性的神经性疼痛，而针对T细胞和瘦素的治疗可能对女性有性别依赖性的益处。
