Gyoneva Stefka, Kim Daniel, Katsumoto Atsuko, Kokiko-Cochran O Nicole, Lamb Bruce T, Ransohoff Richard M
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
Neuroinflammation Research Center, Cleveland Clinic Foundation, Cleveland, OH, USA.
J Neuroinflammation. 2015 Dec 3;12:228. doi: 10.1186/s12974-015-0443-0.
Millions of people experience traumatic brain injury (TBI) as a result of falls, car accidents, sports injury, and blast. TBI has been associated with the development of neurodegenerative conditions such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). In the initial hours and days, the pathology of TBI comprises neuronal injury, breakdown of the blood-brain barrier, and inflammation. At the cellular level, the inflammatory reaction consists of responses by brain-resident microglia, astrocytes, and vascular elements as well as infiltration of peripheral cells. After TBI, signaling by chemokine (C-C motif) ligand 2 (CCL2) to the chemokine (C-C motif) receptor 2 (CCR2) is a key regulator of brain infiltration by monocytes.
We utilized mice with one or both copies of Ccr2 disrupted by red fluorescent protein (RFP, Ccr2 (RFP/+) and Ccr2 (RFP/RFP) ). We subjected these mice to the mild lateral fluid percussion model of TBI and examined several pathological outcomes 3 days later in order to determine the effects of altered monocyte entry into the brain.
Ccr2 deletion reduced monocyte infiltration, diminished lesion cavity volume, and lessened axonal damage after mild TBI, but the microglial reaction to the lesion was not affected. We further examined phosphorylation of the microtubule-associated protein tau, which aggregates in brains of people with TBI, AD, and CTE. Surprisingly, Ccr2 deletion was associated with increased tau mislocalization to the cell body in the cortex and hippocampus by tissue staining and increased levels of phosphorylated tau in the hippocampus by Western blot.
Disruption of CCR2 enhanced tau pathology and reduced cavity volume in the context of TBI. The data reveal a complex role for CCR2(+) monocytes in TBI, as monitored by cavity volume, axonal damage, and tau phosphorylation.
数百万人因跌倒、车祸、运动损伤和爆炸而遭受创伤性脑损伤（TBI）。TBI与神经退行性疾病如阿尔茨海默病（AD）和慢性创伤性脑病（CTE）的发生有关。在最初的数小时和数天内，TBI的病理表现包括神经元损伤、血脑屏障破坏和炎症。在细胞水平上，炎症反应包括脑内常驻小胶质细胞、星形胶质细胞和血管成分的反应以及外周细胞的浸润。TBI后，趋化因子（C-C基序）配体2（CCL2）向趋化因子（C-C基序）受体2（CCR2）的信号传导是单核细胞脑内浸润的关键调节因子。
我们使用了一个或两个Ccr2拷贝被红色荧光蛋白破坏的小鼠（RFP，Ccr2（RFP/+）和Ccr2（RFP/RFP））。我们将这些小鼠用于TBI的轻度侧方流体冲击模型，并在3天后检查了几种病理结果，以确定单核细胞进入脑内改变的影响。
Ccr2缺失减少了轻度TBI后的单核细胞浸润、病变腔体积，并减轻了轴突损伤，但小胶质细胞对病变的反应未受影响。我们进一步检查了微管相关蛋白tau的磷酸化，tau在TBI、AD和CTE患者的脑中聚集。令人惊讶的是，通过组织染色，Ccr2缺失与皮质和海马体中tau错误定位到细胞体增加有关，并且通过蛋白质免疫印迹法，海马体中磷酸化tau水平增加。
在TBI的情况下，CCR2的破坏增强了tau病理并减少了腔体积。数据揭示了CCR2（+）单核细胞在TBI中的复杂作用，通过腔体积、轴突损伤和tau磷酸化进行监测。
