Melatonin Reduces Neuroinflammation and Improves Axonal Hypomyelination by Modulating M1/M2 Microglia Polarization via JAK2-STAT3-Telomerase Pathway in Postnatal Rats Exposed to Lipopolysaccharide
Microglia activation and associated inflammation are implicated in the periventricular white matter damage (PWMD) in septic postnatal rats. This study investigated whether melatonin would mitigate inflammation and alleviate the axonal hypomyelination in the corpus callosum in septic postnatal rats....
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| Veröffentlicht in: | Molecular neurobiology 2021-12, Vol.58 (12), p.6552-6576 |
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| creator | Zhou, Qiuping Lin, Lanfen Li, Haiyan Wang, Huifang Jiang, Shuqi Huang, Peixian Lin, Qiongyu Chen, Xuan Deng, Yiyu |
| description | Microglia activation and associated inflammation are implicated in the periventricular white matter damage (PWMD) in septic postnatal rats. This study investigated whether melatonin would mitigate inflammation and alleviate the axonal hypomyelination in the corpus callosum in septic postnatal rats. We further explored if this might be related to the modulation of microglial polarization from M1 phenotype to M2 through the JAK2/STAT3/telomerase pathway. We reported here that indeed melatonin not only can it reduce the neurobehavioral disturbances in LPS-injected rats, but it can also dampen microglia-mediated inflammation. Thus, in LPS + melatonin group, the expression of proinflammatory mediators in M1 phenotype microglia was downregulated. As opposed to this, M2 microglia were increased which was accompanied by upregulated expression of anti-inflammatory mediators along with telomerase reverse transcriptase or melatonin receptor 1(MT1). In parallel to this was decreased NG2 expression but increased expression of myelin and neurofilament proteins. Melatonin can improve hypomyelination which was confirmed by electron microscopy. In vitro in primary microglia stimulated by LPS, melatonin decreased the expression of proinflammatory mediators significantly; but it increased the expression of anti-inflammatory mediators. Additionally, the expression levels of p-JAK2 and p-STAT3 were significantly elevated in microglia after melatonin treatment. Remarkably, the effect of melatonin on LPS-treated microglia was blocked by melatonin receptor, JAK2, STAT3 and telomerase reverse transcriptase inhibitors, respectively. Taken together, it is concluded that melatonin can attenuate PWMD through shifting M1 microglia towards M2 via MT1/JAK2/STAT3/telomerase pathway. The results suggest a new therapeutic strategy whereby melatonin may be adopted to convert microglial polarization from M1 to M2 phenotype that would ultimately contribute to the attenuation of PWMD. |
| doi_str_mv | 10.1007/s12035-021-02568-7 |
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This study investigated whether melatonin would mitigate inflammation and alleviate the axonal hypomyelination in the corpus callosum in septic postnatal rats. We further explored if this might be related to the modulation of microglial polarization from M1 phenotype to M2 through the JAK2/STAT3/telomerase pathway. We reported here that indeed melatonin not only can it reduce the neurobehavioral disturbances in LPS-injected rats, but it can also dampen microglia-mediated inflammation. Thus, in LPS + melatonin group, the expression of proinflammatory mediators in M1 phenotype microglia was downregulated. As opposed to this, M2 microglia were increased which was accompanied by upregulated expression of anti-inflammatory mediators along with telomerase reverse transcriptase or melatonin receptor 1(MT1). In parallel to this was decreased NG2 expression but increased expression of myelin and neurofilament proteins. Melatonin can improve hypomyelination which was confirmed by electron microscopy. In vitro in primary microglia stimulated by LPS, melatonin decreased the expression of proinflammatory mediators significantly; but it increased the expression of anti-inflammatory mediators. Additionally, the expression levels of p-JAK2 and p-STAT3 were significantly elevated in microglia after melatonin treatment. Remarkably, the effect of melatonin on LPS-treated microglia was blocked by melatonin receptor, JAK2, STAT3 and telomerase reverse transcriptase inhibitors, respectively. Taken together, it is concluded that melatonin can attenuate PWMD through shifting M1 microglia towards M2 via MT1/JAK2/STAT3/telomerase pathway. The results suggest a new therapeutic strategy whereby melatonin may be adopted to convert microglial polarization from M1 to M2 phenotype that would ultimately contribute to the attenuation of PWMD.</description><identifier>ISSN: 0893-7648</identifier><identifier>ISSN: 1559-1182</identifier><identifier>EISSN: 1559-1182</identifier><identifier>DOI: 10.1007/s12035-021-02568-7</identifier><identifier>PMID: 34585328</identifier><language>eng</language><publisher>New York: Springer US</publisher><subject>Animals ; Anti-Inflammatory Agents - pharmacology ; Anti-Inflammatory Agents - therapeutic use ; Axons - drug effects ; Axons - metabolism ; Biomedical and Life Sciences ; Biomedicine ; Cell Biology ; Cell Polarity - drug effects ; Corpus callosum ; Electron microscopy ; Genotype & phenotype ; Inflammation ; Janus kinase 2 ; Janus Kinase 2 - metabolism ; Life Sciences & Biomedicine ; Lipopolysaccharides ; Lipopolysaccharides - pharmacology ; Melatonin ; Melatonin - pharmacology ; Melatonin - therapeutic use ; Microglia ; Microglia - drug effects ; Microglia - metabolism ; Myelin ; Myelin Sheath - drug effects ; Myelin Sheath - metabolism ; Neurobiology ; Neuroinflammatory Diseases - drug therapy ; Neuroinflammatory Diseases - metabolism ; Neurology ; Neuroprotective Agents - pharmacology ; Neuroprotective Agents - therapeutic use ; Neurosciences ; Neurosciences & Neurology ; Phenotypes ; Polarization ; Rats ; RNA-directed DNA polymerase ; Science & Technology ; Signal Transduction - drug effects ; Stat3 protein ; STAT3 Transcription Factor - metabolism ; Substantia alba ; Telomerase ; Telomerase - metabolism ; Telomerase reverse transcriptase ; White Matter - drug effects ; White Matter - metabolism</subject><ispartof>Molecular neurobiology, 2021-12, Vol.58 (12), p.6552-6576</ispartof><rights>The Author(s) 2021</rights><rights>2021. The Author(s).</rights><rights>The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>44</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000701639500003</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c474t-509277a40dc66ec708898d40e21bb4c74ba38567d0b47816b755f74b2ef2b1bf3</citedby><cites>FETCH-LOGICAL-c474t-509277a40dc66ec708898d40e21bb4c74ba38567d0b47816b755f74b2ef2b1bf3</cites><orcidid>0000-0002-0459-7399</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s12035-021-02568-7$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s12035-021-02568-7$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,315,781,785,886,27929,27930,39263,41493,42562,51324</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34585328$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhou, Qiuping</creatorcontrib><creatorcontrib>Lin, Lanfen</creatorcontrib><creatorcontrib>Li, Haiyan</creatorcontrib><creatorcontrib>Wang, Huifang</creatorcontrib><creatorcontrib>Jiang, Shuqi</creatorcontrib><creatorcontrib>Huang, Peixian</creatorcontrib><creatorcontrib>Lin, Qiongyu</creatorcontrib><creatorcontrib>Chen, Xuan</creatorcontrib><creatorcontrib>Deng, Yiyu</creatorcontrib><title>Melatonin Reduces Neuroinflammation and Improves Axonal Hypomyelination by Modulating M1/M2 Microglia Polarization via JAK2-STAT3-Telomerase Pathway in Postnatal Rats Exposed to Lipopolysaccharide</title><title>Molecular neurobiology</title><addtitle>Mol Neurobiol</addtitle><addtitle>MOL NEUROBIOL</addtitle><addtitle>Mol Neurobiol</addtitle><description>Microglia activation and associated inflammation are implicated in the periventricular white matter damage (PWMD) in septic postnatal rats. This study investigated whether melatonin would mitigate inflammation and alleviate the axonal hypomyelination in the corpus callosum in septic postnatal rats. We further explored if this might be related to the modulation of microglial polarization from M1 phenotype to M2 through the JAK2/STAT3/telomerase pathway. We reported here that indeed melatonin not only can it reduce the neurobehavioral disturbances in LPS-injected rats, but it can also dampen microglia-mediated inflammation. Thus, in LPS + melatonin group, the expression of proinflammatory mediators in M1 phenotype microglia was downregulated. As opposed to this, M2 microglia were increased which was accompanied by upregulated expression of anti-inflammatory mediators along with telomerase reverse transcriptase or melatonin receptor 1(MT1). In parallel to this was decreased NG2 expression but increased expression of myelin and neurofilament proteins. Melatonin can improve hypomyelination which was confirmed by electron microscopy. In vitro in primary microglia stimulated by LPS, melatonin decreased the expression of proinflammatory mediators significantly; but it increased the expression of anti-inflammatory mediators. Additionally, the expression levels of p-JAK2 and p-STAT3 were significantly elevated in microglia after melatonin treatment. Remarkably, the effect of melatonin on LPS-treated microglia was blocked by melatonin receptor, JAK2, STAT3 and telomerase reverse transcriptase inhibitors, respectively. Taken together, it is concluded that melatonin can attenuate PWMD through shifting M1 microglia towards M2 via MT1/JAK2/STAT3/telomerase pathway. The results suggest a new therapeutic strategy whereby melatonin may be adopted to convert microglial polarization from M1 to M2 phenotype that would ultimately contribute to the attenuation of PWMD.</description><subject>Animals</subject><subject>Anti-Inflammatory Agents - pharmacology</subject><subject>Anti-Inflammatory Agents - therapeutic use</subject><subject>Axons - drug effects</subject><subject>Axons - metabolism</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cell Biology</subject><subject>Cell Polarity - drug effects</subject><subject>Corpus callosum</subject><subject>Electron microscopy</subject><subject>Genotype & phenotype</subject><subject>Inflammation</subject><subject>Janus kinase 2</subject><subject>Janus Kinase 2 - metabolism</subject><subject>Life Sciences & Biomedicine</subject><subject>Lipopolysaccharides</subject><subject>Lipopolysaccharides - pharmacology</subject><subject>Melatonin</subject><subject>Melatonin - pharmacology</subject><subject>Melatonin - 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This study investigated whether melatonin would mitigate inflammation and alleviate the axonal hypomyelination in the corpus callosum in septic postnatal rats. We further explored if this might be related to the modulation of microglial polarization from M1 phenotype to M2 through the JAK2/STAT3/telomerase pathway. We reported here that indeed melatonin not only can it reduce the neurobehavioral disturbances in LPS-injected rats, but it can also dampen microglia-mediated inflammation. Thus, in LPS + melatonin group, the expression of proinflammatory mediators in M1 phenotype microglia was downregulated. As opposed to this, M2 microglia were increased which was accompanied by upregulated expression of anti-inflammatory mediators along with telomerase reverse transcriptase or melatonin receptor 1(MT1). In parallel to this was decreased NG2 expression but increased expression of myelin and neurofilament proteins. Melatonin can improve hypomyelination which was confirmed by electron microscopy. In vitro in primary microglia stimulated by LPS, melatonin decreased the expression of proinflammatory mediators significantly; but it increased the expression of anti-inflammatory mediators. Additionally, the expression levels of p-JAK2 and p-STAT3 were significantly elevated in microglia after melatonin treatment. Remarkably, the effect of melatonin on LPS-treated microglia was blocked by melatonin receptor, JAK2, STAT3 and telomerase reverse transcriptase inhibitors, respectively. Taken together, it is concluded that melatonin can attenuate PWMD through shifting M1 microglia towards M2 via MT1/JAK2/STAT3/telomerase pathway. The results suggest a new therapeutic strategy whereby melatonin may be adopted to convert microglial polarization from M1 to M2 phenotype that would ultimately contribute to the attenuation of PWMD.</abstract><cop>New York</cop><pub>Springer US</pub><pmid>34585328</pmid><doi>10.1007/s12035-021-02568-7</doi><tpages>25</tpages><orcidid>https://orcid.org/0000-0002-0459-7399</orcidid><oa>free_for_read</oa></addata></record> |
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| ispartof | Molecular neurobiology, 2021-12, Vol.58 (12), p.6552-6576 |
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| subjects | Animals Anti-Inflammatory Agents - pharmacology Anti-Inflammatory Agents - therapeutic use Axons - drug effects Axons - metabolism Biomedical and Life Sciences Biomedicine Cell Biology Cell Polarity - drug effects Corpus callosum Electron microscopy Genotype & phenotype Inflammation Janus kinase 2 Janus Kinase 2 - metabolism Life Sciences & Biomedicine Lipopolysaccharides Lipopolysaccharides - pharmacology Melatonin Melatonin - pharmacology Melatonin - therapeutic use Microglia Microglia - drug effects Microglia - metabolism Myelin Myelin Sheath - drug effects Myelin Sheath - metabolism Neurobiology Neuroinflammatory Diseases - drug therapy Neuroinflammatory Diseases - metabolism Neurology Neuroprotective Agents - pharmacology Neuroprotective Agents - therapeutic use Neurosciences Neurosciences & Neurology Phenotypes Polarization Rats RNA-directed DNA polymerase Science & Technology Signal Transduction - drug effects Stat3 protein STAT3 Transcription Factor - metabolism Substantia alba Telomerase Telomerase - metabolism Telomerase reverse transcriptase White Matter - drug effects White Matter - metabolism |
| title | Melatonin Reduces Neuroinflammation and Improves Axonal Hypomyelination by Modulating M1/M2 Microglia Polarization via JAK2-STAT3-Telomerase Pathway in Postnatal Rats Exposed to Lipopolysaccharide |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-14T23%3A42%3A07IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_webof&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Melatonin%20Reduces%20Neuroinflammation%20and%20Improves%20Axonal%20Hypomyelination%20by%20Modulating%20M1/M2%20Microglia%20Polarization%20via%20JAK2-STAT3-Telomerase%20Pathway%20in%20Postnatal%20Rats%20Exposed%20to%20Lipopolysaccharide&rft.jtitle=Molecular%20neurobiology&rft.au=Zhou,%20Qiuping&rft.date=2021-12-01&rft.volume=58&rft.issue=12&rft.spage=6552&rft.epage=6576&rft.pages=6552-6576&rft.issn=0893-7648&rft.eissn=1559-1182&rft_id=info:doi/10.1007/s12035-021-02568-7&rft_dat=%3Cproquest_webof%3E2605425378%3C/proquest_webof%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2605425378&rft_id=info:pmid/34585328&rfr_iscdi=true |