Recombinant annexin A2 inhibits peripheral leukocyte activation and brain infiltration after traumatic brain injury.
Recombinant annexin A2 inhibits peripheral leukocyte activation and brain infiltration after traumatic brain injury.
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重组膜联蛋白A2抑制创伤性脑损伤后外周血白细胞活化和脑浸润
DOI：
10.1186/s12974-021-02219-7
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发表时间：
2021-08-09
影响因子：
9.3
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Liu N;Han J;Li Y;Jiang Y;Shi SX;Lok J;Whalen M;Dumont AS;Wang X
创伤性脑损伤（TBI）是世界范围内死亡和残疾的重要原因。TLR 4-NFκB信号级联是TBI后白细胞重要的促炎激活通路，调控该信号级联可能是治疗TBI的有效靶点。以往的研究表明，重组膜联蛋白A2（rA 2）可能是一个相互作用的分子，调节TLR 4-NFκB信号通路，然而，rA 2在TBI后白细胞中调节该信号通路的作用及其后续效应尚未研究。使C57 BL/6小鼠经受TBI并随机分成在TBI后2小时接受腹膜内rA 2或载体的组。通过流式细胞术、RT-qPCR和免疫染色检测外周血白细胞活化和浸润免疫细胞。流式细胞术和共聚焦显微镜检测细胞膜上TLR 4的表达，免疫共沉淀结合Western blotting检测annexin A2与TLR 4的相互作用。通过细胞因子蛋白质组分析仪阵列和RT-qPCR测量神经炎症。通过蛋白质印迹和免疫染色确定神经退行性变。神经行为评估用于监测运动和认知功能。通过MAP 2染色评估脑组织损失。在TBI后2小时给予rA 2显著减弱了TBI后24小时的中性粒细胞活化和脑浸润。体内和体外研究结果表明，rA 2在创伤后12 h可与中性粒细胞表面结合并降低其表面TLR 4的表达，抑制中性粒细胞TLR 4/NFκB信号通路。此外，rA 2给药还减少了TBI后24小时内脑组织的促炎症反应和48小时的神经变性。最后，rA 2改善了长期的感觉运动能力和认知功能，并减少了TBI后28天的脑组织损失。全身rA 2管理TBI后2小时显着抑制激活和脑浸润的外周血白细胞，特别是中性粒细胞在急性期。因此，rA 2减少了有害的脑促炎症相关的神经变性，并最终改善TBI后的神经功能缺损。其潜在的分子机制可能至少部分归因于rA 2与外周血白细胞中的促炎受体TLR 4结合，从而阻断TBI后NFκB信号转导激活途径。在线版本包含补充材料，可通过10.1186/s12974-021-02219-7获得。
Traumatic brain injury (TBI) is a significant cause of death and disability worldwide. The TLR4-NFκB signaling cascade is the critical pro-inflammatory activation pathway of leukocytes after TBI, and modulating this signaling cascade may be an effective therapeutic target for treating TBI. Previous studies indicate that recombinant annexin A2 (rA2) might be an interactive molecule modulating the TLR4-NFκB signaling; however, the role of rA2 in regulating this signaling pathway in leukocytes after TBI and its subsequent effects have not been investigated. C57BL/6 mice were subjected to TBI and randomly divided into groups that received intraperitoneal rA2 or vehicle at 2 h after TBI. The peripheral leukocyte activation and infiltrating immune cells were examined by flow cytometry, RT-qPCR, and immunostaining. The neutrophilic TLR4 expression on the cell membrane was examined by flow cytometry and confocal microscope, and the interaction of annexin A2 with TLR4 was assessed by co-immunoprecipitation coupled with Western blotting. Neuroinflammation was measured via cytokine proteome profiler array and RT-qPCR. Neurodegeneration was determined by Western blotting and immunostaining. Neurobehavioral assessments were used to monitor motor and cognitive function. Brain tissue loss was assessed via MAP2 staining. rA2 administration given at 2 h after TBI significantly attenuates neutrophil activation and brain infiltration at 24 h of TBI. In vivo and in vitro data show that rA2 binds to and reduces TLR4 expression on the neutrophil surface and suppresses TLR4/NFκB signaling pathway in neutrophils at 12 h after TBI. Furthermore, rA2 administration also reduces pro-inflammation of brain tissues within 24 h and neurodegeneration at 48 h after TBI. Lastly, rA2 improves long-term sensorimotor ability and cognitive function, and reduces brain tissue loss at 28 days after TBI. Systematic rA2 administration at 2 h after TBI significantly inhibits activation and brain infiltration of peripheral leukocytes, especially neutrophils at the acute phase. Consequently, rA2 reduces the detrimental brain pro-inflammation-associated neurodegeneration and ultimately ameliorates neurological deficits after TBI. The underlying molecular mechanism might be at least in part attributed to rA2 bindings to pro-inflammatory receptor TLR4 in peripheral leukocytes, thereby blocking NFκB signaling activation pathways following TBI. The online version contains supplementary material available at 10.1186/s12974-021-02219-7.
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