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Chemokine signaling mediated monocyte infiltration affects anxiety-like behavior following blast injury
Brain, Behavior, and Immunity ( IF 15.1 ) Pub Date : 2020-08-01 , DOI: 10.1016/j.bbi.2020.03.029
Madhuvika Murugan 1 , Arunreddy Ravula 1 , Ajay Gandhi 1 , Geetasravya Vegunta 1 , Sushni Mukkamalla 1 , Waleed Mujib 1 , Namas Chandra 1
Affiliation  

The activation of resident microglia and infiltrated monocytes are known potent mediators of chronic neuroinflammation following traumatic brain injury (TBI). In this study, we use a mouse model of blast-induced TBI (bTBI) to investigate whether microglia and monocytes contribute to the neuroinflammatory and behavioral consequences of bTBI. Eight-ten week old mice were subject to moderate TBI (180 kPa) in a shock tube. Using double transgenic CCR2RFP/+: CX3CR1GFP/+ mice, we were able to note that in addition to resident Cx3CR1+ microglia, infiltrating CCR2+ monocytes also contributed to the expanding macrophage population that was observed after bTBI. The microglia activation and monocyte infiltration occurred as early as 4h and lasted up to 30d after blast exposure, suggesting chronic inflammation. The infiltration of monocytes may be partly mediated by chemokine CCL2-CCR2 signaling axis and compromised blood brain barrier permeability. Hence, bTBI-induced infiltration of monocytes and production of IL-1β were prevented in mice lacking CCR2 (CCR2 KO). Finally, this study showed that interference of monocyte infiltration using CCR2 KO, ameliorated the chronic effects of bTBI such as anxiety-like behavior and short-term memory decline. Taken together, these data suggest that bTBI leads to activation of both resident microglia and infiltrated monocytes. The infiltration of monocytes was partly mediated by CCL2-CCR2 signaling, which in turn contributes to increased production of IL-1β leading to behavioral deficits after bTBI. Furthermore, bTBI induced behavioral outcomes were reduced by targeting CCL2-CCR2 signaling, highlighting the significance of this signaling axis in bTBI pathology.

中文翻译:

趋化因子信号介导的单核细胞浸润影响爆炸伤后的焦虑样行为

驻留小胶质细胞和浸润的单核细胞的激活是已知的创伤性脑损伤 (TBI) 后慢性神经炎症的有效介质。在这项研究中,我们使用爆炸诱导 TBI (bTBI) 的小鼠模型来研究小胶质细胞和单核细胞是否有助于 bTBI 的神经炎症和行为后果。八十周大的小鼠在冲击管中接受中度 TBI (180 kPa)。使用双转基因 CCR2RFP/+:CX3CR1GFP/+ 小鼠,我们能够注意到,除了常驻 Cx3CR1+ 小胶质细胞外,浸润的 CCR2+ 单核细胞也有助于在 bTBI 后观察到的巨噬细胞数量增加。小胶质细胞活化和单核细胞浸润早在爆炸暴露后4h就出现了,持续到30d,提示慢性炎症。单核细胞的浸润可能部分由趋化因子 CCL2-CCR2 信号轴介导和受损的血脑屏障通透性。因此,在缺乏 CCR2 (CCR2 KO) 的小鼠中阻止了 bTBI 诱导的单核细胞浸润和 IL-1β 的产生。最后,这项研究表明,使用 CCR2 KO 干扰单核细胞浸润,改善了 bTBI 的慢性影响,例如焦虑样行为和短期记忆下降。总之,这些数据表明 bTBI 导致常驻小胶质细胞和浸润的单核细胞的激活。单核细胞的浸润部分由 CCL2-CCR2 信号传导介导,这反过来又有助于增加 IL-1β 的产生,导致 bTBI 后的行为缺陷。此外,通过靶向 CCL2-CCR2 信号传导降低了 bTBI 诱导的行为结果,
更新日期:2020-08-01
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