Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury.
Time-dependent effects of CX3CR1 in a mouse model of mild traumatic brain injury.
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DOI：
10.1186/s12974-015-0386-5
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发表时间：
2015-09-02
影响因子：
9.3
通讯作者：
Gemma C
中科院分区：
文献类型：
--
作者：
Febinger HY;Thomasy HE;Pavlova MN;Ringgold KM;Barf PR;George AM;Grillo JN;Bachstetter AD;Garcia JA;Cardona AE;Opp MR;Gemma C
神经炎症是一种重要的继发性机制，是创伤性脑损伤（TBI）中发生的神经元损伤的长期后果的关键介质。小胶质细胞是高度可塑性的细胞，在神经元损伤和恢复中具有双重作用。最近的研究表明，趋化因子fractalkine（CX 3CL 1，FKN）通过其唯一的受体CX 3CR 1介导神经/小胶质细胞的相互作用。CX 3CL 1/CX 3CR 1信号调节小胶质细胞活化，并根据损伤的类型和时间，保护或加重神经系统疾病。在这项研究中，CX 3CR 1缺陷的小鼠受到轻度控制的皮质撞击损伤（CCI），一种TBI模型。我们评估了CX 3CR 1基因缺失对损伤后30天的组织病理学、细胞死亡/存活、小胶质细胞活化和认知功能的影响。在急性损伤后阶段（24小时至15天），运动缺陷，细胞死亡和神经元细胞丢失在受伤的野生型比CX 3CR 1 −/−小鼠更深刻。相比之下，在TBI后30天的慢性期内，受伤的CX 3CR 1 −/−小鼠表现出比野生型小鼠更大的认知功能障碍和神经元死亡增加。CX 3CR 1的保护和有害作用与小胶质细胞表型的变化有关;在急性期，CX 3CR 1 −/−小鼠表现出主要的抗炎M2小胶质细胞反应，Ym 1，CD 206和TGFβ的表达增加。相比之下，增加的M1表型小胶质细胞标记物，马可，和CD 68的主要在30天后TBI。总的来说，这些新的数据证明了TBI后CX 3CL 1/CX 3CR 1信号传导的时间依赖性作用，并表明对轻度TBI的急性和慢性反应部分由不同的小胶质细胞表型调节。
Neuroinflammation is an important secondary mechanism that is a key mediator of the long-term consequences of neuronal injury that occur in traumatic brain injury (TBI). Microglia are highly plastic cells with dual roles in neuronal injury and recovery. Recent studies suggest that the chemokine fractalkine (CX3CL1, FKN) mediates neural/microglial interactions via its sole receptor CX3CR1. CX3CL1/CX3CR1 signaling modulates microglia activation, and depending upon the type and time of injury, either protects or exacerbates neurological diseases. In this study, mice deficient in CX3CR1 were subjected to mild controlled cortical impact injury (CCI), a model of TBI. We evaluated the effects of genetic deletion of CX3CR1 on histopathology, cell death/survival, microglia activation, and cognitive function for 30 days post-injury. During the acute post-injury period (24 h–15 days), motor deficits, cell death, and neuronal cell loss were more profound in injured wild-type than in CX3CR1−/− mice. In contrast, during the chronic period of 30 days post-TBI, injured CX3CR1−/− mice exhibited greater cognitive dysfunction and increased neuronal death than wild-type mice. The protective and deleterious effects of CX3CR1 were associated with changes in microglia phenotypes; during the acute phase CX3CR1−/− mice showed a predominant anti-inflammatory M2 microglial response, with increased expression of Ym1, CD206, and TGFβ. In contrast, increased M1 phenotypic microglia markers, Marco, and CD68 were predominant at 30 days post-TBI. Collectively, these novel data demonstrate a time-dependent role for CX3CL1/CX3CR1 signaling after TBI and suggest that the acute and chronic responses to mild TBI are modulated in part by distinct microglia phenotypes.