State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.
Ministry of Education Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China.
J Immunol. 2020 Mar 15;204(6):1486-1498. doi: 10.4049/jimmunol.1900909. Epub 2020 Feb 7.
Microglia play essential roles in neuroinflammatory responses after traumatic brain injury (TBI). Our previous studies showed that phenotypes of microglia, as well as infiltrating macrophages, altered at different stages after CNS injury, which was correlated to functional outcomes. IL-13 is an anti-inflammatory cytokine that has been reported to protect against demyelination and spinal cord injury through immunomodulation. The effects of IL-13 in microglia/macrophage-mediated immune responses after TBI remain unknown. In this study, we showed that intranasal administration of IL-13 in male C57BL/6J mice accelerated functional recovery in the controlled cortical impact model of TBI. IL-13 treatment increased the time to fall off in the Rotarod test, reduced the number of foot faults in the foot fault test, and improved the score in the wire hang test up to 28 d after TBI. Consistent with functional improvement, IL-13 reduced neuronal tissue loss and preserved white matter integrity 6 d after TBI. Furthermore, IL-13 ameliorated the elevation of proinflammatory factors and reduced the number of proinflammatory microglia/macrophages 6 d after TBI. Additionally, IL-13 enhanced microglia/macrophage phagocytosis of damaged neurons in the peri-lesion areas. In vitro studies confirmed that IL-13 treatment inhibited the production of proinflammatory cytokines in rat primary microglia in response to LPS or dead neuron stimulation and increased the ability of microglia to engulf fluorophore-labeled latex beads or dead neurons. Collectively, we demonstrated that IL-13 treatment improved neurologic outcomes after TBI through adjusting microglia/macrophage phenotypes and inhibiting inflammatory responses. IL-13 may represent a potential immunotherapy to promote long-term recovery from TBI.
小胶质细胞在创伤性脑损伤（TBI）后的神经炎症反应中发挥重要作用。我们之前的研究表明，在中枢神经系统损伤后不同阶段，小胶质细胞和浸润的巨噬细胞的表型发生改变，这与功能结果相关。IL-13 是一种抗炎细胞因子，据报道通过免疫调节可防止脱髓鞘和脊髓损伤。IL-13 在 TBI 后小胶质细胞/巨噬细胞介导的免疫反应中的作用尚不清楚。在这项研究中，我们表明，在雄性 C57BL/6J 小鼠中经鼻内给予 IL-13 可加速 TBI 的皮质撞击模型中的功能恢复。IL-13 治疗增加了 Rotarod 测试中跌倒的时间，减少了足部故障测试中的足误次数，并在 TBI 后 28 天提高了悬线测试的分数。与功能改善一致，IL-13 减少了神经元组织损失并保持了 TBI 后 6 天的白质完整性。此外，IL-13 减轻了促炎因子的升高，并减少了 TBI 后 6 天促炎小胶质细胞/巨噬细胞的数量。此外，IL-13 增强了损伤神经元在病变区周围的吞噬作用。体外研究证实，IL-13 处理抑制了 LPS 或死神经元刺激下大鼠原代小胶质细胞中促炎细胞因子的产生，并增加了小胶质细胞吞噬荧光素标记的乳胶珠或死神经元的能力。总之，我们证明了 IL-13 治疗通过调节小胶质细胞/巨噬细胞表型和抑制炎症反应改善了 TBI 后的神经功能。IL-13 可能代表一种潜在的免疫疗法，可促进 TBI 的长期恢复。
