rAAV8-mediated inhibition of miRNA-21 protects mice against the lethal schistosome infection by repressing both IL-13 and TGF-β1 pathways
Identifieur interne : 003581 ( Ncbi/Merge ); précédent : 003580; suivant : 003582rAAV8-mediated inhibition of miRNA-21 protects mice against the lethal schistosome infection by repressing both IL-13 and TGF-β1 pathways
Auteurs : Xing He [République populaire de Chine] ; Jun Xie [États-Unis] ; Dongmei Zhang [République populaire de Chine] ; Qin Su [États-Unis] ; Xue Sai [République populaire de Chine] ; Ruipu Bai [République populaire de Chine] ; Chao Chen [République populaire de Chine] ; Xufeng Luo [République populaire de Chine] ; Guangping Gao [États-Unis] ; Weiqing Pan [République populaire de Chine]Source :
- Hepatology (Baltimore, Md.) [ 0270-9139 ] ; 2015.
Abstract
Schistosomiasis is a serious parasitic disease in humans, which can lead to liver fibrosis and death. Accumulating evidence indicated that targeting the deregulated microRNAs could mitigate disease outcomes. Here, we showed that progressive hepatic schistosomiasis caused elevation of miR-21 and efficient and sustained inhibition of miR-21 by using highly hepatic tropic adeno-associated virus serotype 8 (rAAV8) protected mice against the lethal schistosome infection through the attenuation of hepatic fibrosis. We demonstrated an additive role of IL-13 and TGF-β1 in up-regulating the miR-21 expression in the hepatic stellate cells (HSCs) by activation of the SMAD proteins. Further, the down-regulation of miR-21 in the HSCs reversed hepatic fibrosis by enhancing SMAD7 expression, thus repressing TGF-β1/Smad and IL-13/Smad pathways.
Our study revealed the mechanism of IL-13-mediated schistosomiasis hepatic fibrosis by up-regulation of miR-21 and highlights the potential of rAAV8-mediated miR-21 inhibition as a therapeutic intervention for hepatic fibrotic diseases, such as schistosomiasis.
Url:
DOI: 10.1002/hep.27671
PubMed: 25546547
PubMed Central: 4441614
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Chen</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Luo, Xufeng" sort="Luo, Xufeng" uniqKey="Luo X" first="Xufeng" last="Luo">Xufeng Luo</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Gao, Guangping" sort="Gao, Guangping" uniqKey="Gao G" first="Guangping" last="Gao">Guangping Gao</name><affiliation wicri:level="2"><nlm:aff id="A2">Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="A3">Department of Microbiology and Physiology Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Microbiology and Physiology Systems, University of Massachusetts Medical School, Worcester, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Pan, Weiqing" sort="Pan, Weiqing" uniqKey="Pan W" first="Weiqing" last="Pan">Weiqing Pan</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">25546547</idno><idno type="pmc">4441614</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441614</idno><idno type="RBID">PMC:4441614</idno><idno type="doi">10.1002/hep.27671</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">001993</idno><idno 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Xie</name><affiliation wicri:level="2"><nlm:aff id="A2">Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="A3">Department of Microbiology and Physiology Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Microbiology and Physiology Systems, University of Massachusetts Medical School, Worcester, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Zhang, Dongmei" sort="Zhang, Dongmei" uniqKey="Zhang D" first="Dongmei" last="Zhang">Dongmei Zhang</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Su, Qin" sort="Su, Qin" uniqKey="Su Q" first="Qin" last="Su">Qin Su</name><affiliation wicri:level="2"><nlm:aff id="A2">Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Sai, Xue" sort="Sai, Xue" uniqKey="Sai X" first="Xue" last="Sai">Xue Sai</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Bai, Ruipu" sort="Bai, Ruipu" uniqKey="Bai R" first="Ruipu" last="Bai">Ruipu Bai</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Chen, Chao" sort="Chen, Chao" uniqKey="Chen C" first="Chao" last="Chen">Chao Chen</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Luo, Xufeng" sort="Luo, Xufeng" uniqKey="Luo X" first="Xufeng" last="Luo">Xufeng Luo</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author><author><name sortKey="Gao, Guangping" sort="Gao, Guangping" uniqKey="Gao G" first="Guangping" last="Gao">Guangping Gao</name><affiliation wicri:level="2"><nlm:aff id="A2">Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation><affiliation wicri:level="2"><nlm:aff id="A3">Department of Microbiology and Physiology Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Department of Microbiology and Physiology Systems, University of Massachusetts Medical School, Worcester, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Pan, Weiqing" sort="Pan, Weiqing" uniqKey="Pan W" first="Weiqing" last="Pan">Weiqing Pan</name><affiliation wicri:level="1"><nlm:aff id="A1">Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.</nlm:aff><country xml:lang="fr" wicri:curation="lc">République populaire de Chine</country><wicri:regionArea>Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai</wicri:regionArea><wicri:noRegion>Shanghai</wicri:noRegion></affiliation></author></analytic><series><title level="j">Hepatology (Baltimore, Md.)</title><idno type="ISSN">0270-9139</idno><idno type="eISSN">1527-3350</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p id="P2">Schistosomiasis is a serious parasitic disease in humans, which can lead to liver fibrosis and death. Accumulating evidence indicated that targeting the deregulated microRNAs could mitigate disease outcomes. Here, we showed that progressive hepatic schistosomiasis caused elevation of miR-21 and efficient and sustained inhibition of miR-21 by using highly hepatic tropic adeno-associated virus serotype 8 (rAAV8) protected mice against the lethal schistosome infection through the attenuation of hepatic fibrosis. We demonstrated an additive role of IL-13 and TGF-β1 in up-regulating the miR-21 expression in the hepatic stellate cells (HSCs) by activation of the SMAD proteins. Further, the down-regulation of miR-21 in the HSCs reversed hepatic fibrosis by enhancing SMAD7 expression, thus repressing TGF-β1/Smad and IL-13/Smad pathways.</p><sec id="S1"><title>Conclusion</title><p id="P3">Our study revealed the mechanism of IL-13-mediated schistosomiasis hepatic fibrosis by up-regulation of miR-21 and highlights the potential of rAAV8-mediated miR-21 inhibition as a therapeutic intervention for hepatic fibrotic diseases, such as schistosomiasis.</p></sec></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<pmc-dir>properties manuscript</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-journal-id">8302946</journal-id><journal-id journal-id-type="pubmed-jr-id">4093</journal-id><journal-id journal-id-type="nlm-ta">Hepatology</journal-id><journal-id journal-id-type="iso-abbrev">Hepatology</journal-id><journal-title-group><journal-title>Hepatology (Baltimore, Md.)</journal-title></journal-title-group><issn pub-type="ppub">0270-9139</issn><issn pub-type="epub">1527-3350</issn></journal-meta><article-meta><article-id pub-id-type="pmid">25546547</article-id><article-id pub-id-type="pmc">4441614</article-id><article-id pub-id-type="doi">10.1002/hep.27671</article-id><article-id pub-id-type="manuscript">NIHMS652972</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>rAAV8-mediated inhibition of miRNA-21 protects mice against the lethal schistosome infection by repressing both IL-13 and TGF-β1 pathways</article-title></title-group><contrib-group><contrib contrib-type="author" equal-contrib="yes"><name><surname>He</surname><given-names>Xing</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author" equal-contrib="yes"><name><surname>Xie</surname><given-names>Jun</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Dongmei</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Su</surname><given-names>Qin</given-names></name><xref ref-type="aff" rid="A2">2</xref></contrib><contrib contrib-type="author"><name><surname>Sai</surname><given-names>Xue</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Bai</surname><given-names>Ruipu</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Chao</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Luo</surname><given-names>Xufeng</given-names></name><xref ref-type="aff" rid="A1">1</xref></contrib><contrib contrib-type="author"><name><surname>Gao</surname><given-names>Guangping</given-names></name><xref ref-type="aff" rid="A2">2</xref><xref ref-type="aff" rid="A3">3</xref><xref ref-type="corresp" rid="CR1">#</xref></contrib><contrib contrib-type="author"><name><surname>Pan</surname><given-names>Weiqing</given-names></name><xref ref-type="aff" rid="A1">1</xref><xref ref-type="corresp" rid="CR1">#</xref></contrib></contrib-group><aff id="A1"><label>1</label>Department of Tropical Infectious Diseases, Second Military Medical University, Shanghai, China.</aff><aff id="A2"><label>2</label>Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.</aff><aff id="A3"><label>3</label>Department of Microbiology and Physiology Systems, University of Massachusetts Medical School, Worcester, Massachusetts, USA.</aff><author-notes><fn id="FN1"><p id="P1">Xing He, <email>hexing595@yeah.net</email>; Jun Xie, <email>Jun.Xie@umassmed.edu</email>; Dongmei Zhang, <email>dm_zhangcn@yahoo.com</email>; Qin Su, <email>Qin.Su@umassmed.edu</email>; Xue Sai, <email>saixue@126.com</email>; Ruipu Bai, <email>kuailehaizi@163.com</email>; Chao Chen, <email>chenchao_8713@aliyun.com</email>; Xufeng Luo, <email>xufengluo@gmail.com</email>.</p></fn><corresp id="CR1"><label>#</label>: To whom correspondence should be addressed. <bold>Contact Information</bold> Weiqing Pan Address: Second Military Medical University, 800 Xiang Yin Road, Shanghai, China. Tel: 86-21-81871010 Fax: 86-21-65331272 <email>wapan0912@aliyun.com</email> Guangping Gao Address: Universty of Massachusetts Medical School, 381 Plantation Street, Suite 250, Worcester, Massachusetts, USA. Tel: 508.856.3563 Fax: 508.856.1552 <email>guangping.gao@umassmed.edu</email></corresp></author-notes><pub-date pub-type="nihms-submitted"><day>19</day><month>2</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>15</day><month>4</month><year>2015</year></pub-date><pub-date pub-type="ppub"><month>6</month><year>2015</year></pub-date><pub-date pub-type="pmc-release"><day>01</day><month>6</month><year>2016</year></pub-date><volume>61</volume><issue>6</issue><fpage>2008</fpage><lpage>2017</lpage><pmc-comment>elocation-id from pubmed: 10.1002/hep.27671</pmc-comment>
<abstract><p id="P2">Schistosomiasis is a serious parasitic disease in humans, which can lead to liver fibrosis and death. Accumulating evidence indicated that targeting the deregulated microRNAs could mitigate disease outcomes. Here, we showed that progressive hepatic schistosomiasis caused elevation of miR-21 and efficient and sustained inhibition of miR-21 by using highly hepatic tropic adeno-associated virus serotype 8 (rAAV8) protected mice against the lethal schistosome infection through the attenuation of hepatic fibrosis. We demonstrated an additive role of IL-13 and TGF-β1 in up-regulating the miR-21 expression in the hepatic stellate cells (HSCs) by activation of the SMAD proteins. Further, the down-regulation of miR-21 in the HSCs reversed hepatic fibrosis by enhancing SMAD7 expression, thus repressing TGF-β1/Smad and IL-13/Smad pathways.</p><sec id="S1"><title>Conclusion</title><p id="P3">Our study revealed the mechanism of IL-13-mediated schistosomiasis hepatic fibrosis by up-regulation of miR-21 and highlights the potential of rAAV8-mediated miR-21 inhibition as a therapeutic intervention for hepatic fibrotic diseases, such as schistosomiasis.</p></sec></abstract><kwd-group><kwd>microRNA</kwd><kwd>schistosomiasis</kwd><kwd>hepatic fibrosis</kwd><kwd>SMAD signaling</kwd><kwd>gene therapy</kwd></kwd-group></article-meta></front></pmc><affiliations><list><country><li>République populaire de Chine</li><li>États-Unis</li></country><region><li>Massachusetts</li></region></list><tree><country name="République populaire de Chine"><noRegion><name sortKey="He, Xing" sort="He, Xing" uniqKey="He X" first="Xing" last="He">Xing He</name></noRegion><name sortKey="Bai, Ruipu" sort="Bai, Ruipu" uniqKey="Bai R" first="Ruipu" last="Bai">Ruipu Bai</name><name sortKey="Chen, Chao" sort="Chen, Chao" uniqKey="Chen C" first="Chao" last="Chen">Chao Chen</name><name sortKey="Luo, Xufeng" sort="Luo, Xufeng" uniqKey="Luo X" first="Xufeng" last="Luo">Xufeng Luo</name><name sortKey="Pan, Weiqing" sort="Pan, Weiqing" uniqKey="Pan W" first="Weiqing" last="Pan">Weiqing Pan</name><name sortKey="Sai, Xue" sort="Sai, Xue" uniqKey="Sai X" first="Xue" last="Sai">Xue Sai</name><name sortKey="Zhang, Dongmei" sort="Zhang, Dongmei" uniqKey="Zhang D" first="Dongmei" last="Zhang">Dongmei Zhang</name></country><country name="États-Unis"><region name="Massachusetts"><name sortKey="Xie, Jun" sort="Xie, Jun" uniqKey="Xie J" first="Jun" last="Xie">Jun Xie</name></region><name sortKey="Gao, Guangping" sort="Gao, Guangping" uniqKey="Gao G" first="Guangping" last="Gao">Guangping Gao</name><name sortKey="Gao, Guangping" sort="Gao, Guangping" uniqKey="Gao G" first="Guangping" last="Gao">Guangping Gao</name><name sortKey="Su, Qin" sort="Su, Qin" uniqKey="Su Q" first="Qin" last="Su">Qin Su</name><name sortKey="Xie, Jun" sort="Xie, Jun" uniqKey="Xie J" first="Jun" last="Xie">Jun Xie</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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