Translational Neuroscience Facility, Department of Physiology, School of Biomedical Sciences, University of New South Wales, UNSW Sydney, NSW, Australia.
Translational Neuroscience Facility, Department of Physiology, School of Biomedical Sciences, University of New South Wales, UNSW Sydney, NSW, Australia.
Brain Behav Immun. 2024 Nov;122:287-300. doi: 10.1016/j.bbi.2024.07.043. Epub 2024 Aug 2.
Immune cells are critical in promoting neuroinflammation and neuropathic pain and in facilitating pain resolution, depending on their inflammatory and immunoregulatory cytokine response. Interleukin (IL)-35, secreted by regulatory immune cells, is a member of the IL-12 family with a potent immunosuppressive function. In this study, we investigated the effects of IL-35 on pain behaviors, spinal microglia phenotype following peripheral nerve injury, and in vitro microglial cultures in male and female mice. Intrathecal recombinant IL-35 treatment alleviated mechanical pain hypersensitivity prominently in male mice, with only a modest effect in female mice after sciatic nerve chronic constriction injury (CCI). IL-35 treatment resulted in sex-specific microglial changes following CCI, reducing inflammatory microglial markers and upregulating anti-inflammatory markers in male mice. Spatial transcriptomic analysis revealed that IL-35 suppressed microglial complement activation in the superficial dorsal horn in male mice after CCI. Moreover, in vitro studies showed that IL-35 treatment of cultured inflammatory microglia mitigated their hypertrophied morphology, increased their cell motility, and decreased their phagocytic activity, indicating a phenotypic shift towards homeostatic microglia. Further, IL-35 altered microglial cytokines/chemokines in vitro, suppressing the release of IL-9 and monocyte-chemoattractant protein-1 and increasing IL-10 in the supernatant of male microglial cultures. Our findings indicate that treatment with IL-35 modulates spinal microglia and alleviates neuropathic pain in male mice, suggesting IL-35 as a potential sex-specific targeted immunomodulatory treatment for neuropathic pain.
免疫细胞在促进神经炎症和神经病理性疼痛以及促进疼痛缓解方面起着关键作用，这取决于它们的炎症和免疫调节细胞因子反应。白细胞介素 (IL)-35 由调节性免疫细胞分泌，是 IL-12 家族的一员，具有强大的免疫抑制功能。在本研究中，我们研究了 IL-35 对疼痛行为、外周神经损伤后脊髓小胶质细胞表型以及雄性和雌性小鼠体外小胶质细胞培养的影响。鞘内重组 IL-35 治疗明显缓解了雄性小鼠的机械性疼痛过敏，而在慢性坐骨神经缩窄损伤 (CCI) 后雌性小鼠仅有轻微作用。IL-35 治疗导致 CCI 后雄性小鼠的小胶质细胞发生性别特异性变化，减少了炎症性小胶质细胞标志物，上调了抗炎标志物。空间转录组学分析显示，IL-35 抑制了 CCI 后雄性小鼠背角浅层的小胶质细胞补体激活。此外，体外研究表明，IL-35 处理培养的炎性小胶质细胞减轻了它们的肥大形态，增加了它们的细胞迁移能力，并降低了它们的吞噬活性，表明向稳态小胶质细胞的表型转变。此外，IL-35 改变了体外小胶质细胞细胞因子/趋化因子的释放，抑制了雄性小胶质细胞培养物上清液中 IL-9 和单核细胞趋化蛋白-1 的释放，并增加了 IL-10 的释放。我们的研究结果表明，IL-35 的治疗调节了脊髓小胶质细胞，并缓解了雄性小鼠的神经病理性疼痛，提示 IL-35 作为一种潜在的性别特异性靶向免疫调节治疗神经病理性疼痛的方法。
