CCR2 Deficiency Impairs Macrophage Infiltration and Improves Cognitive Function after Traumatic Brain Injury
CCR2 Deficiency Impairs Macrophage Infiltration and Improves Cognitive Function after Traumatic Brain Injury
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DOI：
10.1089/neu.2013.3252
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发表时间：
2014-10-15
影响因子：
4.2
通讯作者：
Nakamura, Mary C.
中科院分区：
文献类型：
--
作者：
Hsieh, Christine L.;Niemi, Erene C.;Nakamura, Mary C.
创伤性脑损伤（TBI）引起炎症反应，包括损伤区域脑巨噬细胞的急剧增加。巨噬细胞浸润创伤性脑损伤的途径以及巨噬细胞对功能结局的影响尚未完全了解。C-C趋化因子受体2（CCR 2）已知用于将单核细胞引导至发炎组织。为了评估巨噬细胞和CCR 2在TBI中的作用，我们确定了CCR 2缺陷（Ccr 2（-/-））小鼠在受控皮质撞击模型中的结果。我们通过流式细胞术定量TBI后的脑髓样细胞数量，发现与野生型小鼠相比，Ccr 2（-/-）小鼠在TBI后早期巨噬细胞数量大大减少（类似于减少80-90%）。评估运动、运动和认知结果。缺乏Ccr 2改善了运动活动，在开放领域的测试中活动减少，但并没有影响TBI后三周的旋转杆上的焦虑水平或运动协调。重要的是，Ccr 2（-/-）小鼠表现出更大的空间学习和记忆，与野生型小鼠相比，TBI后8周。虽然组织损失的体积没有差异，但与野生型小鼠相比，Ccr 2（-/-）小鼠在TBI后海马CA 1-CA 3区域的神经元密度显著增加。这些数据表明，Ccr 2指导大多数巨噬细胞归巢到脑TBI后早期，并表明Ccr 2可能促进有害的反应。Ccr 2的缺乏改善了功能恢复和神经元存活。这些结果表明，CCR 2依赖性反应的治疗性阻断可以改善TBI后的结局。
Traumatic brain injury (TBI) provokes inflammatory responses, including a dramatic rise in brain macrophages in the area of injury. The pathway(s) responsible for macrophage infiltration of the traumatically injured brain and the effects of macrophages on functional outcomes are not well understood. C-C-chemokine receptor 2 (CCR2) is known for directing monocytes to inflamed tissues. To assess the role of macrophages and CCR2 in TBI, we determined outcomes in CCR2-deficient (Ccr2(-/-)) mice in a controlled cortical impact model. We quantified brain myeloid cell numbers post-TBI by flow cytometry and found that Ccr2(-/-) mice had greatly reduced macrophage numbers (similar to 80-90% reduction) early post-TBI, compared with wild-type mice. Motor, locomotor, and cognitive outcomes were assessed. Lack of Ccr2 improved locomotor activity with less hyperactivity in open field testing, but did not affect anxiety levels or motor coordination on the rotarod three weeks after TBI. Importantly, Ccr2(-/-) mice demonstrated greater spatial learning and memory, compared with wildtype mice eight weeks after TBI. Although there was no difference in the volume of tissue loss, Ccr2(-/-) mice had significantly increased neuronal density in the CA1-CA3 regions of the hippocampus after TBI, compared with wild-type mice. These data demonstrate that Ccr2 directs the majority of macrophage homing to the brain early after TBI and indicates that Ccr2 may facilitate harmful responses. Lack of Ccr2 improves functional recovery and neuronal survival. These results suggest that therapeutic blockade of CCR2-dependent responses may improve outcomes following TBI.