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Partial suppression of M1 microglia by Janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis
BACKGROUND: Accumulating evidence has shown that the inflammatory process participates in the pathogenesis of amyotrophic lateral sclerosis (ALS), suggesting a therapeutic potential of anti-inflammatory agents. Janus kinase 2 (JAK2), one of the key molecules in inflammation, transduces signals downs...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213500/ https://www.ncbi.nlm.nih.gov/pubmed/25326688 http://dx.doi.org/10.1186/s12974-014-0179-2 |
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author | Tada, Satoru Okuno, Tatsusada Hitoshi, Yasumichi Yasui, Teruhito Honorat, Josephe Archie Takata, Kazushiro Koda, Toru Shimagami, Hiroshi Chi-Jing, Choong Namba, Akiko Sugimoto, Tomoyuki Sakoda, Saburo Mochizuki, Hideki Kikutani, Hitoshi Nakatsuji, Yuji |
author_facet | Tada, Satoru Okuno, Tatsusada Hitoshi, Yasumichi Yasui, Teruhito Honorat, Josephe Archie Takata, Kazushiro Koda, Toru Shimagami, Hiroshi Chi-Jing, Choong Namba, Akiko Sugimoto, Tomoyuki Sakoda, Saburo Mochizuki, Hideki Kikutani, Hitoshi Nakatsuji, Yuji |
author_sort | Tada, Satoru |
collection | PubMed |
description | BACKGROUND: Accumulating evidence has shown that the inflammatory process participates in the pathogenesis of amyotrophic lateral sclerosis (ALS), suggesting a therapeutic potential of anti-inflammatory agents. Janus kinase 2 (JAK2), one of the key molecules in inflammation, transduces signals downstream of various inflammatory cytokines, and some Janus kinase inhibitors have already been clinically applied to the treatment of inflammatory diseases. However, the efficacy of JAK2 inhibitors in treatment of ALS remains to be demonstrated. In this study, we examined the role of JAK2 in ALS by administering a selective JAK2 inhibitor, R723, to an animal model of ALS (mSOD1(G93A) mice). FINDINGS: Orally administered R723 had sufficient access to spinal cord tissue of mSOD1(G93A) mice and significantly reduced the number of Ly6c positive blood monocytes, as well as the expression levels of IFN-γ and nitric oxide synthase 2, inducible (iNOS) in the spinal cord tissue. R723 treatment did not alter the expression levels of Il-1β, Il-6, TNF, and NADPH oxidase 2 (NOX2), and suppressed the expression of Retnla, which is one of the markers of neuroprotective M2 microglia. As a result, R723 did not alter disease progression or survival of mSOD1(G93A) mice. CONCLUSIONS: JAK2 inhibitor was not effective against ALS symptoms in mSOD1(G93A) mice, irrespective of suppression in several inflammatory molecules. Simultaneous suppression of anti-inflammatory microglia with a failure to inhibit critical other inflammatory molecules might explain this result. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12974-014-0179-2) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-4213500 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-42135002014-10-31 Partial suppression of M1 microglia by Janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis Tada, Satoru Okuno, Tatsusada Hitoshi, Yasumichi Yasui, Teruhito Honorat, Josephe Archie Takata, Kazushiro Koda, Toru Shimagami, Hiroshi Chi-Jing, Choong Namba, Akiko Sugimoto, Tomoyuki Sakoda, Saburo Mochizuki, Hideki Kikutani, Hitoshi Nakatsuji, Yuji J Neuroinflammation Short Report BACKGROUND: Accumulating evidence has shown that the inflammatory process participates in the pathogenesis of amyotrophic lateral sclerosis (ALS), suggesting a therapeutic potential of anti-inflammatory agents. Janus kinase 2 (JAK2), one of the key molecules in inflammation, transduces signals downstream of various inflammatory cytokines, and some Janus kinase inhibitors have already been clinically applied to the treatment of inflammatory diseases. However, the efficacy of JAK2 inhibitors in treatment of ALS remains to be demonstrated. In this study, we examined the role of JAK2 in ALS by administering a selective JAK2 inhibitor, R723, to an animal model of ALS (mSOD1(G93A) mice). FINDINGS: Orally administered R723 had sufficient access to spinal cord tissue of mSOD1(G93A) mice and significantly reduced the number of Ly6c positive blood monocytes, as well as the expression levels of IFN-γ and nitric oxide synthase 2, inducible (iNOS) in the spinal cord tissue. R723 treatment did not alter the expression levels of Il-1β, Il-6, TNF, and NADPH oxidase 2 (NOX2), and suppressed the expression of Retnla, which is one of the markers of neuroprotective M2 microglia. As a result, R723 did not alter disease progression or survival of mSOD1(G93A) mice. CONCLUSIONS: JAK2 inhibitor was not effective against ALS symptoms in mSOD1(G93A) mice, irrespective of suppression in several inflammatory molecules. Simultaneous suppression of anti-inflammatory microglia with a failure to inhibit critical other inflammatory molecules might explain this result. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12974-014-0179-2) contains supplementary material, which is available to authorized users. BioMed Central 2014-10-19 /pmc/articles/PMC4213500/ /pubmed/25326688 http://dx.doi.org/10.1186/s12974-014-0179-2 Text en © Tada et al.; licensee BioMed Central Ltd. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Short Report Tada, Satoru Okuno, Tatsusada Hitoshi, Yasumichi Yasui, Teruhito Honorat, Josephe Archie Takata, Kazushiro Koda, Toru Shimagami, Hiroshi Chi-Jing, Choong Namba, Akiko Sugimoto, Tomoyuki Sakoda, Saburo Mochizuki, Hideki Kikutani, Hitoshi Nakatsuji, Yuji Partial suppression of M1 microglia by Janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis |
title | Partial suppression of M1 microglia by Janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis |
title_full | Partial suppression of M1 microglia by Janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis |
title_fullStr | Partial suppression of M1 microglia by Janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis |
title_full_unstemmed | Partial suppression of M1 microglia by Janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis |
title_short | Partial suppression of M1 microglia by Janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis |
title_sort | partial suppression of m1 microglia by janus kinase 2 inhibitor does not protect against neurodegeneration in animal models of amyotrophic lateral sclerosis |
topic | Short Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213500/ https://www.ncbi.nlm.nih.gov/pubmed/25326688 http://dx.doi.org/10.1186/s12974-014-0179-2 |
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