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Sci Adv. 2019 May 15;5(5):eaav5086. doi: 10.1126/sciadv.aav5086. eCollection 2019 May.

Macrophage centripetal migration drives spontaneous healing process after spinal cord injury.

Author information

1
Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
2
Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
3
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
4
Department of Orthopedic Surgery, Spinal Injuries Center, Iizuka, Japan.
5
Division of Transcriptomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
6
Program in Genomics of Differentiation, NICHD, National Institutes of Health, Bethesda, MD, USA.
7
Department of Molecular and System Pharmacology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
8
Department of Life Innovation, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
9
Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
10
Kyushu Rosai Hospital, Kitakyushu, Japan.

Abstract

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.

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