||Masuda Takahiro, Nao Nishimoto, Daisuke Tomiyama, Tsuyoshi Matsuda, Hidetoshi Saitoh, Tomohiko Tamura, Shinichi Kohsaka, TSUDA MAKOTO, Kazuhide Inoue, IRF8 is a transcriptional determinant for microglial motility. , Purinergic Signal., [Epub ahead of print], 2014.05.
||Masuda Takahiro, Shosuke Iwamoto, Ryohei Yoshinaga, Hidetoshi Saitoh, A. Nishiyama, T. W. Mak, T. Tamura, TSUDA MAKOTO, Kazuhide Inoue, Transcription factor IRF5 drives P2X4R+ reactive microglia gating neuropathic pain. , Nat Commun., doi: 10.1038/ncomms4771., 13;5:3771. , 2014.05.
||Katsuyuki Matsushita, Chinami Kojima, Hidetoshi Saitoh, TSUDA MAKOTO, Kazuhide Inoue, Sumio Hoka, C-C chemokine receptor type 5 is an important pathological regulator in the development and maintenance of neuropathic pain. , Anesthesiology, DOI: 10.1097 /ALN.0000000000000190, 120, 6, 1491-1503, [Epub ahead of print], 2014.02, Background: Chemokine family are revealed to be involved in the pathogenesis of neuropathic pain. In this study, we investigated the role of C-C chemokine ligand 3 (CCL3) and its receptors C-C chemokine receptor type 1 (CCR1) and C-C chemokine receptor type 5 (CCR5) in neuropathic pain.
Materials and Methods: Adult male Wistar rats were used. Spinal nerve injury model was used as a model of neuropathic pain. CCL3 neutralizing antibody, CCR1 antagonist or CCR5 antagonist were administered. Von Frey test and hot plate test were applied to evaluate the neuropathic pain behavior. Real-time quantitative RT-PCR, in situ hybridization, immunohistochemistry were also performed to clarify molecular mechanisms.
Results: Expression levels of CCL3 and CCR5 mRNA in the spinal cord were upregulated after nerve injury. CD11b/c positive microglia were suggested to be responsible for these upregulation. Single intrathecal administration of recombinant CCL3 produced biphasic tactile allodynia-like behavior. The first phase reaction was suppressed by CCR1 antagonist pretreatment, and the second phase reaction was suppressed by CCR5 antagonist pretreatment. Intrathecal injection of CCL3 neutralizing antibody or CCR5 antagonist, successfully suppressed the development of tactile allodynia. Intrathecal injection of CCL3 neutralizing antibody or CCR5 antagonist could reverse the established tactile allodynia. CCR1 antagonist had transient effect to reverse tactile allodynia. Furthermore, oral administration of CCR5 antagonist was effective to established tactile allodynia.
Conclusions: Pharmacological blockade of CCR5 was effective in the development and maintenance of neuropathic pain. Thus, CCR5 antagonist may be a potential new drug for the treatment of neuropathic pain..
||Nakaya Michio, Tajima M, Kosako H, Nakaya T, Hashimoto A, Watari K, Nishihara H, Ohba M, Komiya S, Tani N, Motohiro Nishida, Taniguchi H, Sato Y, Matsumoto M, TSUDA MAKOTO, Kuroda M, Kazuhide Inoue, Hitoshi Kurose, GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance., Nat Commun., doi: 10.1038/ncomms2540., 4:1532., 2013.02.
||Sun L, Wu Z, Yoshinori Hayashi, Peters C, TSUDA MAKOTO, Kazuhide Inoue, Hiroshi Nakanishi, Microglial cathepsin B contributes to the initiation of peripheral inflammation-induced chronic pain., J Neurosci, 32(33):11330-42., 2012.08.
||Masuda Takahiro, TSUDA MAKOTO, Ryohei Yoshinaga, Hidetoshi Saitoh, K. Ozato, T. Tamura, Kazuhide Inoue, IRF8 is a critical transcription factor for transforming microglia into a reactive phenotype., Cell Rep., doi: 10.1016/j.celrep.2012.02.014., 1(4):334-40, 2012.04, Microglia become activated by multiple types of damage in the nervous system and play essential roles in neuronal pathologies. However, how microglia transform into reactive phenotypes is poorly understood. Here, we identify the transcription factor interferon regulatory factor 8 (IRF8) as a critical regulator of reactive microglia. Within the spinal cord, IRF8 expression was normally low; however, the expression was markedly upregulated in microglia, but not in neurons or astrocytes, after peripheral nerve injury (PNI). IRF8 overexpression in cultured microglia promoted the transcription of genes associated with reactive states; conversely, IRF8 deficiency prevented these gene expressions in the spinal cord following PNI. Furthermore, IRF8-deficient mice were resistant to neuropathic pain, a common sequela of PNI, and transferring IRF8-overexpressing microglia spinally to normal mice produced pain. Therefore, IRF8 may activate a program of gene expression that transforms microglia into a reactive phenotype. Our findings provide a newly observed mechanism for microglial activation..
||Y. Hayashi, K. Kawaji, L. Sun, X. Zhang, K. Koyano, T. Yokoyama, S.Kohsaka, K. Inoue, and H. Nakanishi., Microglial Ca2+-activated K+ Channels Are Possible Molecular Targets for the Analgesic Effects of S-ketamine on Neuropathic Pain., J.Neurosci, 10.1523/JNEUROSCI.4152-11.2011, 31, 48, 17370-17382, 2011.11.
||Biber K, Tsuda M, Saitoh-Tozaki H, Tsukamoto K, Toyomitsu E, Masuda T, Boddeke H, Inoue K., Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development., EMBO J, 30:1864-73, 2011.05.
||M. Nishida, M. Ogushi, R. Suda, M. Toyotaka, S. Saiki, N. Kitajima, M. Nakaya, K.-M. Kim, T. Ide, Y. Sato, K. Inoue, and H. Kurose., Heterologous down-regulation of angiotensin type 1 receptors by purinergic P2Y2 receptor stimulation through S-nitrosylation of NF-κB, PNAS, 108(16):6662-7, 2011.04.
||M. Tsuda, Y. Kohro, T. Yano, T. Tsujikawa, J. Kitano, H. Tozaki-Saitoh, S. Koyanagi, S. Ohdo, R-R Ji, M. W. Salter, K. Inoue., JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. , Brain, 134(4): 1127-1139, 2011.04.
||M. Tsuda*, T. Masuda*, J. Kitano, H. Shimoyama, H. Tozaki-Saitoh, K. Inoue. *equally contributed., IFN-γ receptor signaling mediates spinal microglia activation driving neuropathic pain. , Pro.Natl.Acad.Sci.USA , 106(19):8032-7, 2009.05.
||Y. Shinozaki, K. Sumitomo, M. Tsuda, S. Koizumi, K. Inoue and K. Torimitsu.
, Direct observation of ATP-induced conformational changes in single P2X4 receptors.
, PLoS Biology , 2009 May 5;7(5):e103. [Epub ahead of print]
||H. Tozaki-Saitoh1, M. Tsuda, H. Miyata, K. Ueda, S. Kohsaka, K. Inoue. , P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. , J.Neurosci., 28:4949-56, 2008.05.
||Coull JAM, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y, BDNF from microglia mediates the shift in neuronal anion gradient that underlies neuropathic pain., Nature, 10.1038/nature04223, 438, 7070, 1017-1021, 438, 1017-1021, 2005.04.
||Koizumi S, Fujishita K, Tsuda M, Shigemoto-Mogami Y, Kita A, Inoue K., Dynamic inhibition of excitatory synaptic transmission by astrocyte-derived ATP in hippocampal cultures., Pro Nat Acad Sci USA, 10.1073/pnas.1834448100, 100, 19, 11023-11028, 100, 11023-11028, 2003.04.
||Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K., P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury., Nature, 10.1038/nature01786, 424, 6950, 778-783, 424, 778-783, 2003.04.