Autophagy inhibition-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis
Identifieur interne : 000A24 ( Main/Merge ); précédent : 000A23; suivant : 000A25Autophagy inhibition-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in pulmonary fibrosis
Auteurs : Charlotte Hill ; Juanjuan Li ; Dian Liu [République populaire de Chine] ; Franco Conforti ; Christopher J. Brereton ; Liudi Yao ; Yilu Zhou ; Aiman Alzetani ; Serena J. Chee ; Ben G. Marshall ; Sophie V. Fletcher ; David Hancock ; Christian H. Ottensmeier ; Andrew J. Steele ; Julian Downward ; Luca Richeldi [Italie] ; Xin Lu ; Donna E. Davies ; Mark G. Jones ; Yihua Wang [République populaire de Chine]Source :
- Cell Death & Disease [ 2041-4889 ] ; 2019.
Abstract
Idiopathic pulmonary fibrosis (IPF), the prototypic progressive fibrotic interstitial lung disease, is thought to be a consequence of repetitive micro-injuries to an ageing, susceptible alveolar epithelium. Ageing is a risk factor for IPF and incidence has been demonstrated to increase with age. Decreased (macro)autophagy with age has been reported extensively in a variety of systems and diseases, including IPF. However, it is undetermined whether the role of faulty autophagy is causal or coincidental in the context of IPF. Here, we report that in alveolar epithelial cells inhibition of autophagy promotes epithelial–mesenchymal transition (EMT), a process implicated in embryonic development, wound healing, cancer metastasis and fibrosis. We further demonstrate that this is attained, at least in part, by increased p62/SQSTM1 expression that promotes p65/RELA mediated-transactivation of an EMT transcription factor, Snail2 (
Url:
DOI: 10.1038/s41419-019-1820-x
PubMed: 31391462
PubMed Central: 6685977
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PMC:6685977Le document en format XML
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<author><name sortKey="Li, Juanjuan" sort="Li, Juanjuan" uniqKey="Li J" first="Juanjuan" last="Li">Juanjuan Li</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id>
<institution-id institution-id-type="GRID">grid.5491.9</institution-id>
<institution>Biological Sciences, Faculty of Environmental and Life Sciences,</institution>
<institution>University of Southampton,</institution>
</institution-wrap>
Southampton, SO17 1BJ UK</nlm:aff>
<wicri:noCountry code="subfield">SO17 1BJ UK</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Liu, Dian" sort="Liu, Dian" uniqKey="Liu D" first="Dian" last="Liu">Dian Liu</name>
<affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 7223</institution-id>
<institution-id institution-id-type="GRID">grid.33199.31</institution-id>
<institution>Department of Oncology, Tongji Hospital, Tongji Medical College,</institution>
<institution>Huazhong University of Science and Technology,</institution>
</institution-wrap>
Wuhan, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Wuhan</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Conforti, Franco" sort="Conforti, Franco" uniqKey="Conforti F" first="Franco" last="Conforti">Franco Conforti</name>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id>
<institution-id institution-id-type="GRID">grid.5491.9</institution-id>
<institution>Clinical and Experimental Sciences, Faculty of Medicine,</institution>
<institution>University of Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
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<institution-id institution-id-type="GRID">grid.123047.3</institution-id>
<institution>NIHR Southampton Biomedical Research Centre,</institution>
<institution>University Hospital Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Brereton, Christopher J" sort="Brereton, Christopher J" uniqKey="Brereton C" first="Christopher J." last="Brereton">Christopher J. Brereton</name>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id>
<institution-id institution-id-type="GRID">grid.5491.9</institution-id>
<institution>Clinical and Experimental Sciences, Faculty of Medicine,</institution>
<institution>University of Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id>
<institution-id institution-id-type="GRID">grid.123047.3</institution-id>
<institution>NIHR Southampton Biomedical Research Centre,</institution>
<institution>University Hospital Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Yao, Liudi" sort="Yao, Liudi" uniqKey="Yao L" first="Liudi" last="Yao">Liudi Yao</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id>
<institution-id institution-id-type="GRID">grid.5491.9</institution-id>
<institution>Biological Sciences, Faculty of Environmental and Life Sciences,</institution>
<institution>University of Southampton,</institution>
</institution-wrap>
Southampton, SO17 1BJ UK</nlm:aff>
<wicri:noCountry code="subfield">SO17 1BJ UK</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Zhou, Yilu" sort="Zhou, Yilu" uniqKey="Zhou Y" first="Yilu" last="Zhou">Yilu Zhou</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id>
<institution-id institution-id-type="GRID">grid.5491.9</institution-id>
<institution>Biological Sciences, Faculty of Environmental and Life Sciences,</institution>
<institution>University of Southampton,</institution>
</institution-wrap>
Southampton, SO17 1BJ UK</nlm:aff>
<wicri:noCountry code="subfield">SO17 1BJ UK</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Alzetani, Aiman" sort="Alzetani, Aiman" uniqKey="Alzetani A" first="Aiman" last="Alzetani">Aiman Alzetani</name>
<affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id>
<institution-id institution-id-type="GRID">grid.123047.3</institution-id>
<institution>NIHR Southampton Biomedical Research Centre,</institution>
<institution>University Hospital Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id>
<institution-id institution-id-type="GRID">grid.123047.3</institution-id>
<institution>University Hospital Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Chee, Serena J" sort="Chee, Serena J" uniqKey="Chee S" first="Serena J." last="Chee">Serena J. Chee</name>
<affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id>
<institution-id institution-id-type="GRID">grid.123047.3</institution-id>
<institution>University Hospital Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id>
<institution-id institution-id-type="GRID">grid.5491.9</institution-id>
<institution>Cancer Sciences Unit,</institution>
<institution>University of Southampton,</institution>
</institution-wrap>
Somers Building, Southampton General Hospital, Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Marshall, Ben G" sort="Marshall, Ben G" uniqKey="Marshall B" first="Ben G." last="Marshall">Ben G. Marshall</name>
<affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id>
<institution-id institution-id-type="GRID">grid.123047.3</institution-id>
<institution>NIHR Southampton Biomedical Research Centre,</institution>
<institution>University Hospital Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id>
<institution-id institution-id-type="GRID">grid.123047.3</institution-id>
<institution>University Hospital Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Fletcher, Sophie V" sort="Fletcher, Sophie V" uniqKey="Fletcher S" first="Sophie V." last="Fletcher">Sophie V. Fletcher</name>
<affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id>
<institution-id institution-id-type="GRID">grid.123047.3</institution-id>
<institution>NIHR Southampton Biomedical Research Centre,</institution>
<institution>University Hospital Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff5"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id>
<institution-id institution-id-type="GRID">grid.123047.3</institution-id>
<institution>University Hospital Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Hancock, David" sort="Hancock, David" uniqKey="Hancock D" first="David" last="Hancock">David Hancock</name>
<affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1795 1830</institution-id>
<institution-id institution-id-type="GRID">grid.451388.3</institution-id>
<institution>Oncogene Biology,</institution>
<institution>The Francis Crick Institute,</institution>
</institution-wrap>
London, NW1 1AT UK</nlm:aff>
<wicri:noCountry code="subfield">NW1 1AT UK</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Ottensmeier, Christian H" sort="Ottensmeier, Christian H" uniqKey="Ottensmeier C" first="Christian H." last="Ottensmeier">Christian H. Ottensmeier</name>
<affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id>
<institution-id institution-id-type="GRID">grid.123047.3</institution-id>
<institution>NIHR Southampton Biomedical Research Centre,</institution>
<institution>University Hospital Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id>
<institution-id institution-id-type="GRID">grid.5491.9</institution-id>
<institution>Cancer Sciences Unit,</institution>
<institution>University of Southampton,</institution>
</institution-wrap>
Somers Building, Southampton General Hospital, Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Steele, Andrew J" sort="Steele, Andrew J" uniqKey="Steele A" first="Andrew J." last="Steele">Andrew J. Steele</name>
<affiliation><nlm:aff id="Aff6"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id>
<institution-id institution-id-type="GRID">grid.5491.9</institution-id>
<institution>Cancer Sciences Unit,</institution>
<institution>University of Southampton,</institution>
</institution-wrap>
Somers Building, Southampton General Hospital, Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Downward, Julian" sort="Downward, Julian" uniqKey="Downward J" first="Julian" last="Downward">Julian Downward</name>
<affiliation><nlm:aff id="Aff7"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1795 1830</institution-id>
<institution-id institution-id-type="GRID">grid.451388.3</institution-id>
<institution>Oncogene Biology,</institution>
<institution>The Francis Crick Institute,</institution>
</institution-wrap>
London, NW1 1AT UK</nlm:aff>
<wicri:noCountry code="subfield">NW1 1AT UK</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Richeldi, Luca" sort="Richeldi, Luca" uniqKey="Richeldi L" first="Luca" last="Richeldi">Luca Richeldi</name>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id>
<institution-id institution-id-type="GRID">grid.5491.9</institution-id>
<institution>Clinical and Experimental Sciences, Faculty of Medicine,</institution>
<institution>University of Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id>
<institution-id institution-id-type="GRID">grid.123047.3</institution-id>
<institution>NIHR Southampton Biomedical Research Centre,</institution>
<institution>University Hospital Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff8"><institution-wrap><institution-id institution-id-type="ISNI">0000 0001 0941 3192</institution-id>
<institution-id institution-id-type="GRID">grid.8142.f</institution-id>
<institution>Unità Operativa Complessa di Pneumologia,</institution>
<institution>Università Cattolica del Sacro Cuore, Fondazione Policlinico A Gemelli IRCCS,</institution>
</institution-wrap>
Rome, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Rome</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lu, Xin" sort="Lu, Xin" uniqKey="Lu X" first="Xin" last="Lu">Xin Lu</name>
<affiliation><nlm:aff id="Aff9"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 8948</institution-id>
<institution-id institution-id-type="GRID">grid.4991.5</institution-id>
<institution>Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine,</institution>
<institution>University of Oxford,</institution>
</institution-wrap>
Oxford, OX3 7DQ UK</nlm:aff>
<wicri:noCountry code="subfield">OX3 7DQ UK</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Davies, Donna E" sort="Davies, Donna E" uniqKey="Davies D" first="Donna E." last="Davies">Donna E. Davies</name>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id>
<institution-id institution-id-type="GRID">grid.5491.9</institution-id>
<institution>Clinical and Experimental Sciences, Faculty of Medicine,</institution>
<institution>University of Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id>
<institution-id institution-id-type="GRID">grid.123047.3</institution-id>
<institution>NIHR Southampton Biomedical Research Centre,</institution>
<institution>University Hospital Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id>
<institution-id institution-id-type="GRID">grid.5491.9</institution-id>
<institution>Institute for Life Sciences,</institution>
<institution>University of Southampton,</institution>
</institution-wrap>
Southampton, SO17 1BJ UK</nlm:aff>
<wicri:noCountry code="subfield">SO17 1BJ UK</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Jones, Mark G" sort="Jones, Mark G" uniqKey="Jones M" first="Mark G." last="Jones">Mark G. Jones</name>
<affiliation><nlm:aff id="Aff3"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id>
<institution-id institution-id-type="GRID">grid.5491.9</institution-id>
<institution>Clinical and Experimental Sciences, Faculty of Medicine,</institution>
<institution>University of Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff4"><institution-wrap><institution-id institution-id-type="ISNI">0000000103590315</institution-id>
<institution-id institution-id-type="GRID">grid.123047.3</institution-id>
<institution>NIHR Southampton Biomedical Research Centre,</institution>
<institution>University Hospital Southampton,</institution>
</institution-wrap>
Southampton, SO16 6YD UK</nlm:aff>
<wicri:noCountry code="subfield">SO16 6YD UK</wicri:noCountry>
</affiliation>
<affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id>
<institution-id institution-id-type="GRID">grid.5491.9</institution-id>
<institution>Institute for Life Sciences,</institution>
<institution>University of Southampton,</institution>
</institution-wrap>
Southampton, SO17 1BJ UK</nlm:aff>
<wicri:noCountry code="subfield">SO17 1BJ UK</wicri:noCountry>
</affiliation>
</author>
<author><name sortKey="Wang, Yihua" sort="Wang, Yihua" uniqKey="Wang Y" first="Yihua" last="Wang">Yihua Wang</name>
<affiliation><nlm:aff id="Aff1"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id>
<institution-id institution-id-type="GRID">grid.5491.9</institution-id>
<institution>Biological Sciences, Faculty of Environmental and Life Sciences,</institution>
<institution>University of Southampton,</institution>
</institution-wrap>
Southampton, SO17 1BJ UK</nlm:aff>
<wicri:noCountry code="subfield">SO17 1BJ UK</wicri:noCountry>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="Aff2"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 0368 7223</institution-id>
<institution-id institution-id-type="GRID">grid.33199.31</institution-id>
<institution>Department of Oncology, Tongji Hospital, Tongji Medical College,</institution>
<institution>Huazhong University of Science and Technology,</institution>
</institution-wrap>
Wuhan, China</nlm:aff>
<country xml:lang="fr">République populaire de Chine</country>
<wicri:regionArea>Wuhan</wicri:regionArea>
</affiliation>
<affiliation><nlm:aff id="Aff10"><institution-wrap><institution-id institution-id-type="ISNI">0000 0004 1936 9297</institution-id>
<institution-id institution-id-type="GRID">grid.5491.9</institution-id>
<institution>Institute for Life Sciences,</institution>
<institution>University of Southampton,</institution>
</institution-wrap>
Southampton, SO17 1BJ UK</nlm:aff>
<wicri:noCountry code="subfield">SO17 1BJ UK</wicri:noCountry>
</affiliation>
</author>
</analytic>
<series><title level="j">Cell Death & Disease</title>
<idno type="eISSN">2041-4889</idno>
<imprint><date when="2019">2019</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
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</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p id="Par1">Idiopathic pulmonary fibrosis (IPF), the prototypic progressive fibrotic interstitial lung disease, is thought to be a consequence of repetitive micro-injuries to an ageing, susceptible alveolar epithelium. Ageing is a risk factor for IPF and incidence has been demonstrated to increase with age. Decreased (macro)autophagy with age has been reported extensively in a variety of systems and diseases, including IPF. However, it is undetermined whether the role of faulty autophagy is causal or coincidental in the context of IPF. Here, we report that in alveolar epithelial cells inhibition of autophagy promotes epithelial–mesenchymal transition (EMT), a process implicated in embryonic development, wound healing, cancer metastasis and fibrosis. We further demonstrate that this is attained, at least in part, by increased p62/SQSTM1 expression that promotes p65/RELA mediated-transactivation of an EMT transcription factor, Snail2 (<italic>SNAI2</italic>
), which not only controls EMT but also regulates the production of locally acting profibrogenic mediators. Our data suggest that reduced autophagy induces EMT of alveolar epithelial cells and can contribute to fibrosis via aberrant epithelial–fibroblast crosstalk.</p>
</div>
</front>
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</author>
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</biblStruct>
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