TY - JOUR
T1 - Anti-IL-6-receptor antibody promotes repair of spinal cord injury by inducing microglia-dominant inflammation
AU - Mukaino, Masahiko
AU - Nakamura, Masaya
AU - Yamada, Osamu
AU - Okada, Seiji
AU - Morikawa, Satoru
AU - Renault-Mihara, Francois
AU - Iwanami, Akio
AU - Ikegami, Takeshi
AU - Ohsugi, Yoshiyuki
AU - Tsuji, Osahiko
AU - Katoh, Hiroyuki
AU - Matsuzaki, Yumi
AU - Toyama, Yoshiaki
AU - Liu, Meigen
AU - Okano, Hideyuki
N1 - Funding Information:
This work was supported by grants from the Project for the Realization of Regenerative Medicine from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan to H.O.; the General Insurance Association of Japan to M.N., A.I. and Y.T.; and a Grant-in-Aid for the Global COE Program from MEXT to Keio University. This work was also supported by grants from the Grant of Orthopaedics and Traumatology Foundation, Inc. No. 0178 to A.I. We are grateful to Professor Claude Bernard at Monash University for his critical reading of the manuscript.
PY - 2010/8
Y1 - 2010/8
N2 - We previously reported the beneficial effect of administering an anti-mouse IL-6 receptor antibody (MR16-1) immediately after spinal cord injury (SCI). The purpose of our present study was to clarify the mechanism underlying how MR16-1 improves motor function after SCI. Quantitative analyses of inflammatory cells using flow cytometry, and immunohistochemistry with bone marrow-chimeric mice generated by transplanting genetically marked purified hematopoietic stem cells, revealed that MR16-1 dramatically switched the central player in the post-traumatic inflammation, from hematogenous macrophages to resident microglia. This change was accompanied by alterations in the expression of relevant cytokines within the injured spinal cord; the expression of recruiting chemokines including CCL2, CCL5, and CXCL10 was decreased, while that of Granulocyte/Macrophage-Colony Stimulating Factor (GM-CSF), a known mitogen for microglia, was increased. We also showed that the resident microglia expressed higher levels of phagocytic markers than the hematogenous macrophages. Consistent with these findings, we observed significantly decreased tissue damage and reduced levels of myelin debris and Nogo-A, the axonal growth inhibitor, by MR16-1 treatment. Moreover, we observed increased axonal regeneration and/or sprouting in the MR16-1-treated mice. Our findings indicate that the functional improvement elicited by MR16-1 involves microglial functions, and provide new insights into the role of IL-6 signaling in the pathology of SCI.
AB - We previously reported the beneficial effect of administering an anti-mouse IL-6 receptor antibody (MR16-1) immediately after spinal cord injury (SCI). The purpose of our present study was to clarify the mechanism underlying how MR16-1 improves motor function after SCI. Quantitative analyses of inflammatory cells using flow cytometry, and immunohistochemistry with bone marrow-chimeric mice generated by transplanting genetically marked purified hematopoietic stem cells, revealed that MR16-1 dramatically switched the central player in the post-traumatic inflammation, from hematogenous macrophages to resident microglia. This change was accompanied by alterations in the expression of relevant cytokines within the injured spinal cord; the expression of recruiting chemokines including CCL2, CCL5, and CXCL10 was decreased, while that of Granulocyte/Macrophage-Colony Stimulating Factor (GM-CSF), a known mitogen for microglia, was increased. We also showed that the resident microglia expressed higher levels of phagocytic markers than the hematogenous macrophages. Consistent with these findings, we observed significantly decreased tissue damage and reduced levels of myelin debris and Nogo-A, the axonal growth inhibitor, by MR16-1 treatment. Moreover, we observed increased axonal regeneration and/or sprouting in the MR16-1-treated mice. Our findings indicate that the functional improvement elicited by MR16-1 involves microglial functions, and provide new insights into the role of IL-6 signaling in the pathology of SCI.
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U2 - 10.1016/j.expneurol.2010.04.020
DO - 10.1016/j.expneurol.2010.04.020
M3 - Article
C2 - 20478301
AN - SCOPUS:77954659876
SN - 0014-4886
VL - 224
SP - 403
EP - 414
JO - Experimental Neurology
JF - Experimental Neurology
IS - 2
ER -