Anti-IL-6-receptor antibody promotes repair of spinal cord injury by inducing microglia-dominant inflammation

Masahiko Mukaino, Masaya Nakamura, Osamu Yamada, Seiji Okada, Satoru Morikawa, Francois Renault-Mihara, Akio Iwanami, Takeshi Ikegami, Yoshiyuki Ohsugi, Osahiko Tsuji, Hiroyuki Katoh, Yumi Matsuzaki, Yoshiaki Toyama, Meigen Liu, Hideyuki Okano

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)403-414
Number of pages12
JournalExperimental Neurology
Volume224
Issue number2
DOIs
Publication statusPublished - 01-08-2010

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Interleukin-6 Receptors
Microglia
Spinal Cord Injuries
Inflammation
Antibodies
Macrophages
Growth Inhibitors
Chemokine CCL2
Granulocyte-Macrophage Colony-Stimulating Factor
Myelin Sheath
Hematopoietic Stem Cells
Mitogens
Regeneration
Interleukin-6
Spinal Cord
Flow Cytometry
Bone Marrow
Immunohistochemistry
Pathology
Cytokines

All Science Journal Classification (ASJC) codes

  • Neurology
  • Developmental Neuroscience

Cite this

Mukaino, Masahiko ; Nakamura, Masaya ; Yamada, Osamu ; Okada, Seiji ; Morikawa, Satoru ; Renault-Mihara, Francois ; Iwanami, Akio ; Ikegami, Takeshi ; Ohsugi, Yoshiyuki ; Tsuji, Osahiko ; Katoh, Hiroyuki ; Matsuzaki, Yumi ; Toyama, Yoshiaki ; Liu, Meigen ; Okano, Hideyuki. / Anti-IL-6-receptor antibody promotes repair of spinal cord injury by inducing microglia-dominant inflammation. In: Experimental Neurology. 2010 ; Vol. 224, No. 2. pp. 403-414.
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abstract = "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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Mukaino, M, Nakamura, M, Yamada, O, Okada, S, Morikawa, S, Renault-Mihara, F, Iwanami, A, Ikegami, T, Ohsugi, Y, Tsuji, O, Katoh, H, Matsuzaki, Y, Toyama, Y, Liu, M & Okano, H 2010, 'Anti-IL-6-receptor antibody promotes repair of spinal cord injury by inducing microglia-dominant inflammation', Experimental Neurology, vol. 224, no. 2, pp. 403-414. https://doi.org/10.1016/j.expneurol.2010.04.020

Anti-IL-6-receptor antibody promotes repair of spinal cord injury by inducing microglia-dominant inflammation. / Mukaino, Masahiko; Nakamura, Masaya; Yamada, Osamu; Okada, Seiji; Morikawa, Satoru; Renault-Mihara, Francois; Iwanami, Akio; Ikegami, Takeshi; Ohsugi, Yoshiyuki; Tsuji, Osahiko; Katoh, Hiroyuki; Matsuzaki, Yumi; Toyama, Yoshiaki; Liu, Meigen; Okano, Hideyuki.

In: Experimental Neurology, Vol. 224, No. 2, 01.08.2010, p. 403-414.

Research output: Contribution to journalArticle

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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

PY - 2010/8/1

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