Cathepsin B aggravates coxsackievirus B3-induced myocarditis through activating the inflammasome and promoting pyroptosis
Cathepsin B (CatB) is a cysteine proteolytic enzyme widely expressed in various cells and mainly located in the lysosomes. It contributes to the pathogenesis and development of many diseases. However, the role of CatB in viral myocarditis (VMC) has never been elucidated. Here we generated the VMC mo...
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| description | Cathepsin B (CatB) is a cysteine proteolytic enzyme widely expressed in various cells and mainly located in the lysosomes. It contributes to the pathogenesis and development of many diseases. However, the role of CatB in viral myocarditis (VMC) has never been elucidated. Here we generated the VMC model by intraperitoneal injection of coxsackievirus B3 (CVB3) into mice. At day 7 and day 28, we found CatB was significantly activated in hearts from VMC mice. Compared with the wild-type mice receiving equal amount of CVB3, genetic ablation of CatB (Ctsb-/-) significantly improved survival, reduced inflammatory cell infiltration, decreased serum level of cardiac troponin I, and ameliorated cardiac dysfunction, without altering virus titers in hearts. Conversely, genetic deletion of cystatin C (Cstc-/-), which markedly enhanced CatB levels in hearts, distinctly increased the severity of VMC. Furthermore, compared with the control, we found the inflammasome was activated in the hearts of wild-type mice with VMC, which was attenuated in the hearts of Ctsb-/- mice but was further enhanced in Cstc-/- mice. Consistently, the inflammasome-initiated pyroptosis was reduced in Ctsb-/- mice hearts and further increased in Cstc-/- mice. These results suggest that CatB aggravates CVB3-induced VMC probably through activating the inflammasome and promoting pyroptosis. This finding might provide a novel strategy for VMC treatment. |
| doi_str_mv | 10.1371/journal.ppat.1006872 |
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It contributes to the pathogenesis and development of many diseases. However, the role of CatB in viral myocarditis (VMC) has never been elucidated. Here we generated the VMC model by intraperitoneal injection of coxsackievirus B3 (CVB3) into mice. At day 7 and day 28, we found CatB was significantly activated in hearts from VMC mice. Compared with the wild-type mice receiving equal amount of CVB3, genetic ablation of CatB (Ctsb-/-) significantly improved survival, reduced inflammatory cell infiltration, decreased serum level of cardiac troponin I, and ameliorated cardiac dysfunction, without altering virus titers in hearts. Conversely, genetic deletion of cystatin C (Cstc-/-), which markedly enhanced CatB levels in hearts, distinctly increased the severity of VMC. Furthermore, compared with the control, we found the inflammasome was activated in the hearts of wild-type mice with VMC, which was attenuated in the hearts of Ctsb-/- mice but was further enhanced in Cstc-/- mice. Consistently, the inflammasome-initiated pyroptosis was reduced in Ctsb-/- mice hearts and further increased in Cstc-/- mice. These results suggest that CatB aggravates CVB3-induced VMC probably through activating the inflammasome and promoting pyroptosis. This finding might provide a novel strategy for VMC treatment.</description><identifier>ISSN: 1553-7374</identifier><identifier>ISSN: 1553-7366</identifier><identifier>EISSN: 1553-7374</identifier><identifier>DOI: 10.1371/journal.ppat.1006872</identifier><identifier>PMID: 29360865</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Analysis ; Animals ; Apoptosis ; Autophagy ; Biology and Life Sciences ; Calcium-binding protein ; Cancer ; Cardiology ; Cardiomyopathy ; Care and treatment ; Caspase 1 - metabolism ; Cathepsin B ; Cathepsin B - genetics ; Cathepsin B - physiology ; Cathepsins ; Cell survival ; Clonal deletion ; Coxsackievirus infections ; Coxsackievirus Infections - complications ; Coxsackievirus Infections - pathology ; Coxsackieviruses ; Cystatin C ; Development and progression ; Disease ; Disease Models, Animal ; Disease Progression ; Enterovirus B, Human - physiology ; Enzyme Activation ; Funding ; Heart ; Heart diseases ; Heart failure ; HeLa Cells ; Hospitals ; Humans ; Infections ; Infiltration ; Inflammasomes ; Inflammasomes - metabolism ; Inflammation ; Lysosomes ; Male ; Medicine ; Medicine and Health Sciences ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocarditis ; Myocarditis - immunology ; Myocarditis - virology ; Myocardium - pathology ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - pathology ; Myocytes, Cardiac - virology ; Pathogenesis ; Proteolysis ; Pyroptosis ; Pyroptosis - physiology ; Research and Analysis Methods ; Rodents ; Troponin ; Troponin I ; Viruses</subject><ispartof>PLoS pathogens, 2018-01, Vol.14 (1), p.e1006872-e1006872</ispartof><rights>COPYRIGHT 2018 Public Library of Science</rights><rights>2018 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Wang Y, Jia L, Shen J, Wang Y, Fu Z, Su S-a, et al. (2018) Cathepsin B aggravates coxsackievirus B3-induced myocarditis through activating the inflammasome and promoting pyroptosis. PLoS Pathog 14(1): e1006872. https://doi.org/10.1371/journal.ppat.1006872</rights><rights>2018 Wang et al 2018 Wang et al</rights><rights>2018 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Wang Y, Jia L, Shen J, Wang Y, Fu Z, Su S-a, et al. (2018) Cathepsin B aggravates coxsackievirus B3-induced myocarditis through activating the inflammasome and promoting pyroptosis. PLoS Pathog 14(1): e1006872. https://doi.org/10.1371/journal.ppat.1006872</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c727t-f105b8e470abe38a0211cd2a1aab3451fd7e9f74f48cafa0b97bc995cb2932073</citedby><cites>FETCH-LOGICAL-c727t-f105b8e470abe38a0211cd2a1aab3451fd7e9f74f48cafa0b97bc995cb2932073</cites><orcidid>0000-0001-7508-2432 ; 0000-0002-9634-3088</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809100/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809100/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53769,53771,79346,79347</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29360865$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Semler, Bert L.</contributor><creatorcontrib>Wang, Yaping</creatorcontrib><creatorcontrib>Jia, Liangliang</creatorcontrib><creatorcontrib>Shen, Jian</creatorcontrib><creatorcontrib>Wang, Yidong</creatorcontrib><creatorcontrib>Fu, Zurong</creatorcontrib><creatorcontrib>Su, Sheng-An</creatorcontrib><creatorcontrib>Cai, Zhejun</creatorcontrib><creatorcontrib>Wang, Jian-An</creatorcontrib><creatorcontrib>Xiang, Meixiang</creatorcontrib><title>Cathepsin B aggravates coxsackievirus B3-induced myocarditis through activating the inflammasome and promoting pyroptosis</title><title>PLoS pathogens</title><addtitle>PLoS Pathog</addtitle><description>Cathepsin B (CatB) is a cysteine proteolytic enzyme widely expressed in various cells and mainly located in the lysosomes. It contributes to the pathogenesis and development of many diseases. However, the role of CatB in viral myocarditis (VMC) has never been elucidated. Here we generated the VMC model by intraperitoneal injection of coxsackievirus B3 (CVB3) into mice. At day 7 and day 28, we found CatB was significantly activated in hearts from VMC mice. Compared with the wild-type mice receiving equal amount of CVB3, genetic ablation of CatB (Ctsb-/-) significantly improved survival, reduced inflammatory cell infiltration, decreased serum level of cardiac troponin I, and ameliorated cardiac dysfunction, without altering virus titers in hearts. Conversely, genetic deletion of cystatin C (Cstc-/-), which markedly enhanced CatB levels in hearts, distinctly increased the severity of VMC. Furthermore, compared with the control, we found the inflammasome was activated in the hearts of wild-type mice with VMC, which was attenuated in the hearts of Ctsb-/- mice but was further enhanced in Cstc-/- mice. Consistently, the inflammasome-initiated pyroptosis was reduced in Ctsb-/- mice hearts and further increased in Cstc-/- mice. These results suggest that CatB aggravates CVB3-induced VMC probably through activating the inflammasome and promoting pyroptosis. This finding might provide a novel strategy for VMC treatment.</description><subject>Analysis</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Autophagy</subject><subject>Biology and Life Sciences</subject><subject>Calcium-binding protein</subject><subject>Cancer</subject><subject>Cardiology</subject><subject>Cardiomyopathy</subject><subject>Care and treatment</subject><subject>Caspase 1 - metabolism</subject><subject>Cathepsin B</subject><subject>Cathepsin B - genetics</subject><subject>Cathepsin B - physiology</subject><subject>Cathepsins</subject><subject>Cell survival</subject><subject>Clonal deletion</subject><subject>Coxsackievirus infections</subject><subject>Coxsackievirus Infections - complications</subject><subject>Coxsackievirus Infections - pathology</subject><subject>Coxsackieviruses</subject><subject>Cystatin C</subject><subject>Development and progression</subject><subject>Disease</subject><subject>Disease Models, Animal</subject><subject>Disease Progression</subject><subject>Enterovirus B, Human - physiology</subject><subject>Enzyme Activation</subject><subject>Funding</subject><subject>Heart</subject><subject>Heart diseases</subject><subject>Heart failure</subject><subject>HeLa Cells</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Infections</subject><subject>Infiltration</subject><subject>Inflammasomes</subject><subject>Inflammasomes - metabolism</subject><subject>Inflammation</subject><subject>Lysosomes</subject><subject>Male</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Myocarditis</subject><subject>Myocarditis - immunology</subject><subject>Myocarditis - virology</subject><subject>Myocardium - pathology</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myocytes, Cardiac - pathology</subject><subject>Myocytes, Cardiac - virology</subject><subject>Pathogenesis</subject><subject>Proteolysis</subject><subject>Pyroptosis</subject><subject>Pyroptosis - physiology</subject><subject>Research and Analysis Methods</subject><subject>Rodents</subject><subject>Troponin</subject><subject>Troponin I</subject><subject>Viruses</subject><issn>1553-7374</issn><issn>1553-7366</issn><issn>1553-7374</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqVkstu1DAUhiMEoqXwBggisYHFDL7EcbxBakdcRqpA4rK2Thw745LEwXZGnbfH00mrDuoGeWHr-Pv_o3PJspcYLTHl-P2Vm_wA3XIcIS4xQmXFyaPsFDNGF5zy4vG990n2LIQrhApMcfk0OyGClqgq2Wm2W0Hc6DHYIb_IoW09bCHqkCt3HUD9tnpr_RTyC7qwQzMp3eT9zinwjY025HHj3dRuclDRJp0d2hTSuR1MB30PwfU6h6HJR-96d_M97rwbows2PM-eGOiCfjHfZ9mvTx9_rr4sLr99Xq_OLxeKEx4XBiNWV7rgCGpNK0AEY9UQwAA1LRg2DdfC8MIUlQIDqBa8VkIwVaciCeL0LHt98B07F-TctSAJQqTEAgmUiPWBaBxcydHbHvxOOrDyJuB8K8FHqzqdVAqRiqHUvLKghoi6JhoQBqOUIHzv9WHONtW9bpQeoofuyPT4Z7Ab2bqtZBUSaYrJ4O1s4N2fSYcoexuU7joYtJuCxEKgiqUxFgl98w_6cHUz1UIqII3GpbxqbyrPGWECF5TiRC0foNJpdG-VG7SxKX4keHckSEzU17GFKQS5_vH9P9ivx2xxYJV3IXht7nqHkdwv_m2Rcr_4cl78JHt1v-93ottNp38BlvoAuQ</recordid><startdate>20180123</startdate><enddate>20180123</enddate><creator>Wang, Yaping</creator><creator>Jia, Liangliang</creator><creator>Shen, Jian</creator><creator>Wang, Yidong</creator><creator>Fu, Zurong</creator><creator>Su, Sheng-An</creator><creator>Cai, Zhejun</creator><creator>Wang, Jian-An</creator><creator>Xiang, Meixiang</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>ISN</scope><scope>ISR</scope><scope>3V.</scope><scope>7QL</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0001-7508-2432</orcidid><orcidid>https://orcid.org/0000-0002-9634-3088</orcidid></search><sort><creationdate>20180123</creationdate><title>Cathepsin B aggravates coxsackievirus B3-induced myocarditis through activating the inflammasome and promoting pyroptosis</title><author>Wang, Yaping ; Jia, Liangliang ; Shen, Jian ; Wang, Yidong ; Fu, Zurong ; Su, Sheng-An ; Cai, Zhejun ; Wang, Jian-An ; Xiang, Meixiang</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c727t-f105b8e470abe38a0211cd2a1aab3451fd7e9f74f48cafa0b97bc995cb2932073</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Analysis</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Autophagy</topic><topic>Biology and Life Sciences</topic><topic>Calcium-binding protein</topic><topic>Cancer</topic><topic>Cardiology</topic><topic>Cardiomyopathy</topic><topic>Care and treatment</topic><topic>Caspase 1 - metabolism</topic><topic>Cathepsin B</topic><topic>Cathepsin B - genetics</topic><topic>Cathepsin B - physiology</topic><topic>Cathepsins</topic><topic>Cell survival</topic><topic>Clonal deletion</topic><topic>Coxsackievirus infections</topic><topic>Coxsackievirus Infections - complications</topic><topic>Coxsackievirus Infections - pathology</topic><topic>Coxsackieviruses</topic><topic>Cystatin C</topic><topic>Development and progression</topic><topic>Disease</topic><topic>Disease Models, Animal</topic><topic>Disease Progression</topic><topic>Enterovirus B, Human - physiology</topic><topic>Enzyme Activation</topic><topic>Funding</topic><topic>Heart</topic><topic>Heart diseases</topic><topic>Heart failure</topic><topic>HeLa Cells</topic><topic>Hospitals</topic><topic>Humans</topic><topic>Infections</topic><topic>Infiltration</topic><topic>Inflammasomes</topic><topic>Inflammasomes - metabolism</topic><topic>Inflammation</topic><topic>Lysosomes</topic><topic>Male</topic><topic>Medicine</topic><topic>Medicine and Health Sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Myocarditis</topic><topic>Myocarditis - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS pathogens</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wang, Yaping</au><au>Jia, Liangliang</au><au>Shen, Jian</au><au>Wang, Yidong</au><au>Fu, Zurong</au><au>Su, Sheng-An</au><au>Cai, Zhejun</au><au>Wang, Jian-An</au><au>Xiang, Meixiang</au><au>Semler, Bert L.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cathepsin B aggravates coxsackievirus B3-induced myocarditis through activating the inflammasome and promoting pyroptosis</atitle><jtitle>PLoS pathogens</jtitle><addtitle>PLoS Pathog</addtitle><date>2018-01-23</date><risdate>2018</risdate><volume>14</volume><issue>1</issue><spage>e1006872</spage><epage>e1006872</epage><pages>e1006872-e1006872</pages><issn>1553-7374</issn><issn>1553-7366</issn><eissn>1553-7374</eissn><abstract>Cathepsin B (CatB) is a cysteine proteolytic enzyme widely expressed in various cells and mainly located in the lysosomes. It contributes to the pathogenesis and development of many diseases. However, the role of CatB in viral myocarditis (VMC) has never been elucidated. Here we generated the VMC model by intraperitoneal injection of coxsackievirus B3 (CVB3) into mice. At day 7 and day 28, we found CatB was significantly activated in hearts from VMC mice. Compared with the wild-type mice receiving equal amount of CVB3, genetic ablation of CatB (Ctsb-/-) significantly improved survival, reduced inflammatory cell infiltration, decreased serum level of cardiac troponin I, and ameliorated cardiac dysfunction, without altering virus titers in hearts. Conversely, genetic deletion of cystatin C (Cstc-/-), which markedly enhanced CatB levels in hearts, distinctly increased the severity of VMC. Furthermore, compared with the control, we found the inflammasome was activated in the hearts of wild-type mice with VMC, which was attenuated in the hearts of Ctsb-/- mice but was further enhanced in Cstc-/- mice. Consistently, the inflammasome-initiated pyroptosis was reduced in Ctsb-/- mice hearts and further increased in Cstc-/- mice. These results suggest that CatB aggravates CVB3-induced VMC probably through activating the inflammasome and promoting pyroptosis. This finding might provide a novel strategy for VMC treatment.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>29360865</pmid><doi>10.1371/journal.ppat.1006872</doi><orcidid>https://orcid.org/0000-0001-7508-2432</orcidid><orcidid>https://orcid.org/0000-0002-9634-3088</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Analysis Animals Apoptosis Autophagy Biology and Life Sciences Calcium-binding protein Cancer Cardiology Cardiomyopathy Care and treatment Caspase 1 - metabolism Cathepsin B Cathepsin B - genetics Cathepsin B - physiology Cathepsins Cell survival Clonal deletion Coxsackievirus infections Coxsackievirus Infections - complications Coxsackievirus Infections - pathology Coxsackieviruses Cystatin C Development and progression Disease Disease Models, Animal Disease Progression Enterovirus B, Human - physiology Enzyme Activation Funding Heart Heart diseases Heart failure HeLa Cells Hospitals Humans Infections Infiltration Inflammasomes Inflammasomes - metabolism Inflammation Lysosomes Male Medicine Medicine and Health Sciences Mice Mice, Inbred C57BL Mice, Knockout Myocarditis Myocarditis - immunology Myocarditis - virology Myocardium - pathology Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology Myocytes, Cardiac - virology Pathogenesis Proteolysis Pyroptosis Pyroptosis - physiology Research and Analysis Methods Rodents Troponin Troponin I Viruses |
| title | Cathepsin B aggravates coxsackievirus B3-induced myocarditis through activating the inflammasome and promoting pyroptosis |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-23T23%3A23%3A19IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Cathepsin%20B%20aggravates%20coxsackievirus%20B3-induced%20myocarditis%20through%20activating%20the%20inflammasome%20and%20promoting%20pyroptosis&rft.jtitle=PLoS%20pathogens&rft.au=Wang,%20Yaping&rft.date=2018-01-23&rft.volume=14&rft.issue=1&rft.spage=e1006872&rft.epage=e1006872&rft.pages=e1006872-e1006872&rft.issn=1553-7374&rft.eissn=1553-7374&rft_id=info:doi/10.1371/journal.ppat.1006872&rft_dat=%3Cgale_plos_%3EA525914331%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2002619090&rft_id=info:pmid/29360865&rft_galeid=A525914331&rft_doaj_id=oai_doaj_org_article_20c02850086643f29bb2ea01afcc9270&rfr_iscdi=true |