Villapol Sonia, Loane David J, Burns Mark P
Laboratory for Brain Injury and Dementia, Department of Neuroscience, Georgetown University, Washington, District of Columbia.
Department of Anesthesiology, Center for Shock, Trauma, and Anesthesiology Research (STAR), University of Maryland School of Medicine, Baltimore, Maryland.
Glia. 2017 Sep;65(9):1423-1438. doi: 10.1002/glia.23171. Epub 2017 Jun 13.
The activation of resident microglial cells, alongside the infiltration of peripheral macrophages, are key neuroinflammatory responses to traumatic brain injury (TBI) that are directly associated with neuronal death. Sexual disparities in response to TBI have been previously reported; however it is unclear whether a sex difference exists in neuroinflammatory progression after TBI. We exposed male and female mice to moderate-to-severe controlled cortical impact injury and studied glial cell activation in the acute and chronic stages of TBI using immunofluorescence and in situ hybridization analysis. We found that the sex response was completely divergent up to 7 days postinjury. TBI caused a rapid and pronounced cortical microglia/macrophage activation in male mice with a prominent activated phenotype that produced both pro- (IL-1β and TNFα) and anti-inflammatory (Arg1 and TGFβ) cytokines with a single-phase, sustained peak from 1 to 7 days. In contrast, TBI caused a less robust microglia/macrophage phenotype in females with biphasic pro-inflammatory response peaks at 4 h and 7 days, and a delayed anti-inflammatory mRNA peak at 30 days. We further report that female mice were protected against acute cell loss after TBI, with male mice demonstrating enhanced astrogliosis, neuronal death, and increased lesion volume through 7 days post-TBI. Collectively, these findings indicate that TBI leads to a more aggressive neuroinflammatory profile in male compared with female mice during the acute and subacute phases postinjury. Understanding how sex affects the course of neuroinflammation following brain injury is a vital step toward developing personalized and effective treatments for TBI.
驻留小胶质细胞的激活以及外周巨噬细胞的浸润，是创伤性脑损伤（TBI）关键的神经炎症反应，与神经元死亡直接相关。此前已有关于TBI反应中性别差异的报道；然而，TBI后神经炎症进展过程中是否存在性别差异尚不清楚。我们将雄性和雌性小鼠暴露于中度至重度的控制性皮质撞击损伤中，并使用免疫荧光和原位杂交分析研究TBI急性和慢性阶段的神经胶质细胞激活情况。我们发现，在损伤后7天内，性别反应完全不同。TBI导致雄性小鼠皮质小胶质细胞/巨噬细胞迅速且显著激活，具有突出的激活表型，产生促炎（IL-1β和TNFα）和抗炎（Arg1和TGFβ）细胞因子，在1至7天呈现单相持续峰值。相比之下，TBI导致雌性小鼠小胶质细胞/巨噬细胞表型激活较弱，在4小时和7天出现双相促炎反应峰值，在30天出现延迟的抗炎mRNA峰值。我们进一步报告，雌性小鼠在TBI后可免受急性细胞损失，而雄性小鼠在TBI后7天内表现出星形胶质细胞增生增强、神经元死亡增加以及损伤体积增大。总体而言，这些发现表明，在损伤后的急性和亚急性阶段，与雌性小鼠相比，TBI在雄性小鼠中导致更具侵袭性的神经炎症特征。了解性别如何影响脑损伤后神经炎症的进程是开发针对TBI的个性化有效治疗方法的关键一步。
