Deletion of p38 MAPK in microglia blunts trauma-induced inflammatory responses in mice
Deletion of p38 MAPK in microglia blunts trauma-induced inflammatory responses in mice
复制标题
小胶质细胞p38 MAPK基因缺失对小鼠创伤后炎症反应的影响
DOI：
10.1186/s12974-019-1493-5
复制
发表时间：
2019-05-10
影响因子：
9.3
通讯作者：
Van Eldik, Linda J.
中科院分区：
文献类型：
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作者：
Morganti, Josh M.;Goulding, Danielle S.;Van Eldik, Linda J.
创伤性脑损伤（TBI）是美国和世界其他发达国家发病率和死亡率的重要原因。在最初的机械损伤后，大脑的主要先天免疫效应子小胶质细胞启动炎症信号级联和病理生理反应，可导致慢性神经炎症和神经退行性后遗症。小胶质细胞中的p38 MAPK信号通路是对多种疾病相关应激源和损伤条件的炎症反应的关键贡献者。因此，我们在这里测试是否小胶质细胞p38有助于急性和持续的炎症反应引起的局灶性脑外伤。我们使用CX 3CR 1 Cre-lox系统在小胶质细胞中产生p38的条件性细胞特异性敲除，使p38敲除小鼠和野生型小鼠经受受控皮质撞击TBI，并测量急性（1天）和亚急性（7天）损伤后时间点的炎症反应。我们发现，仅在小胶质细胞中缺失p38就足以减弱TBI后的多种促炎反应，显著减少促炎细胞因子/趋化因子的产生和炎性单核细胞向脑中的募集，并防止持续的小胶质细胞形态激活。这些数据提供了强有力的证据，支持小胶质细胞p38在TBI后大脑中慢性和潜在神经毒性促炎环境的传播中的作用。
Traumatic brain injury (TBI) is a significant cause of morbidity and mortality in the USA and other developed countries worldwide. Following the initial mechanical insult, the brain's primary innate immune effector, microglia, initiate inflammatory signaling cascades and pathophysiological responses that can lead to chronic neuroinflammation and neurodegenerative sequelae. The p38 MAPK signaling pathway in microglia is a key contributor to inflammatory responses to diverse disease-relevant stressors and injury conditions. Therefore, we tested here whether microglia p38 contributes to acute and persistent inflammatory responses induced by a focal TBI. We generated conditional cell-specific knockout of p38 in microglia using a CX3CR1 Cre-lox system, subjected the p38 knockout and wild-type mice to a controlled cortical impact TBI, and measured inflammatory responses at acute (1-day) and subacute (7-day) post-injury time points. We found that deletion of p38 in microglia only was sufficient to attenuate multiple pro-inflammatory responses following TBI, notably reducing pro-inflammatory cytokine/chemokine production and recruitment of inflammatory monocytes into the brain and preventing the persistent microglial morphological activation. These data provide strong evidence supporting a role for microglial p38 in propagation of a chronic and potentially neurotoxic pro-inflammatory environment in the brain following TBI.