TY - JOUR
T1 - Macrophage centripetal migration drives spontaneous healing process after spinal cord injury
AU - Kobayakawa, Kazu
AU - Ohkawa, Yasuyuki
AU - Yoshizaki, Shingo
AU - Tamaru, Tetsuya
AU - Saito, Takeyuki
AU - Kijima, Ken
AU - Yokota, Kazuya
AU - Hara, Masamitsu
AU - Kubota, Kensuke
AU - Matsumoto, Yoshihiro
AU - Harimaya, Katsumi
AU - Ozato, Keiko
AU - Masuda, Takahiro
AU - Tsuda, Makoto
AU - Tamura, Tomohiko
AU - Inoue, Kazuhide
AU - Reggie Edgerton, V.
AU - Iwamoto, Yukihide
AU - Nakashima, Yasuharu
AU - Okada, Seiji
N1 - Funding Information:
This work was supported by a Grant-in-Aid for Young Scientist (A/B); JSPS Fellows (14 J01375); Scientific Research on Innovative Areas (Comprehensive Brain Science Network and Foundation of Synapse and Neurocircuit Pathology); Challenging Exploratory Research from the Ministry of Education, Science, Sports, and Culture of Japan; and research foundations from the general insurance association of Japan.
Publisher Copyright:
Copyright © 2019 The Authors.
PY - 2019/5/15
Y1 - 2019/5/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85065865262&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065865262&partnerID=8YFLogxK
U2 - 10.1126/sciadv.aav5086
DO - 10.1126/sciadv.aav5086
M3 - Article
C2 - 31106270
AN - SCOPUS:85065865262
SN - 2375-2548
VL - 5
JO - Science advances
JF - Science advances
IS - 5
M1 - eaav5086
ER -