Febinger Heidi Y, Thomasy Hannah E, Pavlova Maria N, Ringgold Kristyn M, Barf Paulien R, George Amrita M, Grillo Jenna N, Bachstetter Adam D, Garcia Jenny A, Cardona Astrid E, Opp Mark R, Gemma Carmelina
Department of Anesthesiology and Pain Medicine, University of Washington, BOX # 359724, Seattle, WA, 98001, USA.
Present address: Interdepartmental Program in Neuroscience, University of Utah School of Medicine, Salt Lake City, Utah, USA.
J Neuroinflammation. 2015 Sep 2;12:154. doi: 10.1186/s12974-015-0386-5.
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.
神经炎症是一种重要的继发性机制，是创伤性脑损伤（TBI）中神经元损伤长期后果的关键介质。小胶质细胞是具有高度可塑性的细胞，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（CX3CL1，FKN）通过其唯一的受体CX3CR1介导神经/小胶质细胞相互作用。CX3CL1/CX3CR1信号传导调节小胶质细胞的激活，并且根据损伤的类型和时间，对神经疾病起到保护或加重的作用。
在本研究中，对CX3CR1基因缺陷的小鼠进行轻度控制性皮质撞击损伤（CCI），这是一种TBI模型。我们评估了CX3CR1基因缺失对损伤后30天的组织病理学、细胞死亡/存活、小胶质细胞激活和认知功能的影响。
在急性损伤后时期（24小时至15天），受伤的野生型小鼠的运动功能缺陷、细胞死亡和神经元细胞损失比CX3CR1（-/-）小鼠更严重。相比之下，在TBI后30天的慢性期，受伤的CX3CR1（-/-）小鼠比野生型小鼠表现出更严重的认知功能障碍和神经元死亡增加。CX3CR1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，CX3CR1（-/-）小鼠表现出主要的抗炎性M2小胶质细胞反应，Ym1、CD206和TGFβ的表达增加。相比之下，在TBI后30天，M1表型小胶质细胞标志物Marco和CD68的增加占主导地位。
总的来说，这些新数据证明了TBI后CX3CL1/CX3CR1信号传导具有时间依赖性作用，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。
