{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T14:40:58Z","timestamp":1789656058898,"version":"4.0.1"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2021,12,5]],"date-time":"2021-12-05T00:00:00Z","timestamp":1638662400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Aims<\/jats:title>\n                    <jats:p>HEV infection is the most common cause of liver inflammation, but the pathogenic mechanisms remain largely unclear. We aim to explore whether HEV infection activates inflammasomes, crosstalk with antiviral interferon response, and the potential of therapeutic targeting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Approach and Results<\/jats:title>\n                    <jats:p>\n                      We measured IL\u20101\u03b2 secretion, the hallmark of inflammasome activation, in serum of HEV\u2010infected patients and rabbits, and in cultured macrophage cell lines and primary monocyte\u2010derived macrophages. We found that genotypes 3 and 4 HEV infection in rabbits elevated IL\u20101\u03b2 production. A profound increase of IL\u20101\u03b2 secretion was further observed in HEV\u2010infected patients (1,733 \u00b1 1,234 pg\/mL;\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      \u00a0=\u00a070) compared to healthy persons (731 \u00b1 701 pg\/mL;\n                      <jats:italic toggle=\"yes\">n<\/jats:italic>\n                      \u00a0=\u00a070). Given that macrophages are the drivers of inflammatory response, we found that inoculation with infectious HEV particles robustly triggered NOD\u2010like receptor family pyrin domain\u2010containing 3 (NLRP3) inflammasome activation in primary macrophages and macrophage cell lines. We further revealed that the ORF2 capsid protein and the formed integral viral particles are responsible for activating inflammasome response. We also identified NF\u2010\u03baB signaling activation as a key upstream event of HEV\u2010induced NLRP3 inflammasome response. Interestingly, inflammasome activation antagonizes interferon response to facilitate viral replication in macrophages. Pharmacological inhibitors and clinically used steroids can effectively target inflammasome activation. Combining steroids with ribavirin simultaneously inhibits HEV and inflammasome response without cross\u2010interference.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>HEV infection strongly activates NLRP3 inflammasome activation in macrophages, which regulates host innate defense and pathogenesis. Therapeutic targeting of NLRP3, in particular when combined with antiviral agents, represents a viable option for treating severe HEV infection.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/hep.32114","type":"journal-article","created":{"date-parts":[[2021,8,15]],"date-time":"2021-08-15T12:47:53Z","timestamp":1629031673000},"page":"196-212","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":43,"title":["Hepatitis E virus infection activates NOD\u2010like receptor family pyrin domain\u2010containing 3 inflammasome antagonizing interferon response but therapeutically targetable"],"prefix":"10.1097","volume":"75","author":[{"given":"Yang","family":"Li","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Erasmus MC\u2010University Medical Center,Rotterdam,The 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Chinese,PLA General Hospital,Beijing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaochao","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Infectious Disease Centre,School of Basic Medical Sciences,Peking University Health Science Centre,Beijing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaye","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Erasmus MC\u2010University Medical Center,Rotterdam,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunlong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Erasmus MC\u2010University Medical Center,Rotterdam,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengfei","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Erasmus MC\u2010University Medical Center,Rotterdam,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Erasmus MC\u2010University Medical Center,Rotterdam,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yining","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Erasmus MC\u2010University Medical Center,Rotterdam,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhongren","family":"Ma","sequence":"additional","affiliation":[{"name":"Biomedical Research Center,Northwest Minzu University,Lanzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aixia","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory,The Fifth Medical Center of Chinese,PLA General Hospital,Beijing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Infectious Disease Centre,School of Basic Medical Sciences,Peking University Health Science Centre,Beijing,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco J.","family":"Bruno","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Erasmus MC\u2010University Medical Center,Rotterdam,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"de Man","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology,Erasmus MC\u2010University Medical Center,Rotterdam,The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maikel P.","family":"Peppelenbosch","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and 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