Macrophage centripetal migration drives spontaneous healing process after spinal cord injury
Macrophage centripetal migration drives spontaneous healing process after spinal cord injury
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DOI：
10.1126/sciadv.aav5086
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发表时间：
2019-05-01
期刊：
影响因子：
13.6
通讯作者：
Okada, Seiji
中科院分区：
文献类型：
--
作者：
Kobayakawa, Kazu;Ohkawa, Yasuyuki;Okada, Seiji
创伤性脊髓损伤（SCI）从循环血液中将大量炎性细胞（包括巨噬细胞）带入病变，但巨噬细胞时空动力学引起的病理生理影响尚不清楚。在这里，我们表明，巨噬细胞向心性迁移到病变中心后，浸润到广泛的脊髓，这取决于梯度的趋化因子C5 a。然而，缺乏干扰素调节因子8（IRF 8）的巨噬细胞不能向震中迁移，并保持广泛分散在损伤的脊髓中，伴有严重的轴突丢失和很少的髓鞘再生，导致SCI后功能结果较差。延时成像和P2 X/YRs阻断显示，通过IRF 8的巨噬细胞迁移是由参与C5 a定向迁移的嘌呤能受体引起的。相反，药理学促进IRF 8活化促进巨噬细胞向心运动，从而改善SCI恢复。我们的研究结果揭示了巨噬细胞通过IRF 8向心迁移的重要性，为中枢神经系统损伤提供了一个新的治疗靶点。
Traumatic spinal cord injury (SCI) brings numerous inflammatory cells, including macrophages, from the circulating blood to lesions, but pathophysiological impact resulting from spatiotemporal dynamics of macrophages is unknown. Here, we show that macrophages centripetally migrate toward the lesion epicenter after infiltrating into the wide range of spinal cord, depending on the gradient of chemoattractant C5a. However, macrophages lacking interferon regulatory factor 8 (IRF8) cannot migrate toward the epicenter and remain widely scattered in the injured cord with profound axonal loss and little remyelination, resulting in a poor functional outcome after SCI. Time-lapse imaging and P2X/YRs blockade revealed that macrophage migration via IRF8 was caused by purinergic receptors involved in the C5a-directed migration. Conversely, pharmacological promotion of IRF8 activation facilitated macrophage centripetal movement, thereby improving the SCI recovery. Our findings reveal the importance of macrophage centripetal migration via IRF8, providing a novel therapeutic target for central nervous system injury.