Anti-IL-6-receptor antibody promotes repair of spinal cord injury by inducing microglia-dominant inflammation.
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.
Mukaino
Masahiko
M
Department of Rehabilitation Medicine, Keio University School of Medicine, Shinjuku, Tokyo 160-8582, Japan.
Nakamura
Masaya
M
Yamada
Osamu
O
Okada
Seiji
S
Morikawa
Satoru
S
Renault-Mihara
Francois
F
Iwanami
Akio
A
Ikegami
Takeshi
T
Ohsugi
Yoshiyuki
Y
Tsuji
Osahiko
O
Katoh
Hiroyuki
H
Matsuzaki
Yumi
Y
Toyama
Yoshiaki
Y
Liu
Meigen
M
Okano
Hideyuki
H
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018925:Chemokines / Q000096:biosynthesis; D002678:Chimera; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D007249:Inflammation / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects* / Q000276:immunology; D010587:Phagocytosis; D051381:Rats; D019947:Receptors, Interleukin-6 / Q000276:immunology*; D013116:Spinal Cord / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D018925:Chemokines; D019947:Receptors, Interleukin-6; D016178:Granulocyte-Macrophage Colony-Stimulating Factor