title: The NLRP3 Inflammasome and IL-1β Accelerate Immunologically Mediated Pathology in Experimental Viral Fulminant Hepatitis.
abstract: Viral fulminant hepatitis (FH) is a severe disease with high mortality resulting from excessive inflammation in the infected liver. Clinical interventions have been inefficient due to the lack of knowledge for inflammatory pathogenesis in the virus-infected liver. We show that wild-type mice infected with murine hepatitis virus strain-3 (MHV-3), a model for viral FH, manifest with severe disease and high mortality in association with a significant elevation in IL-1β expression in the serum and liver. Whereas, the viral infection in IL-1β receptor-I deficient (IL-1R1-/-) or IL-1R antagonist (IL-1Ra) treated mice, show reductions in virus replication, disease progress and mortality. IL-1R1 deficiency appears to debilitate the virus-induced fibrinogen-like protein-2 (FGL2) production in macrophages and CD45+Gr-1high neutrophil infiltration in the liver. The quick release of reactive oxygen species (ROS) by the infected macrophages suggests a plausible viral initiation of NLRP3 inflammasome activation. Further experiments show that mice deficient of p47phox, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit that controls acute ROS production, present with reductions in NLRP3 inflammasome activation and subsequent IL-1β secretion during viral infection, which appears to be responsible for acquiring resilience to viral FH. Moreover, viral infected animals in deficiencies of NLRP3 and Caspase-1, two essential components of the inflammasome complex, also have reduced IL-1β induction along with ameliorated hepatitis. Our results demonstrate that the ROS/NLRP3/IL-1β axis institutes an essential signaling pathway, which is over activated and directly causes the severe liver disease during viral infection, which sheds light on development of efficient treatments for human viral FH and other severe inflammatory diseases.
authors.affiliation: Institute of Immunology, PLA, Third Military Medical University, Chongqing, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Guo
authors.affiliation: Institute of Immunology, PLA, Third Military Medical University, Chongqing, China.
authors.forename: Chengying
authors.initials: C
authors.lastname: Yang
authors.affiliation: Institute of Immunology, PLA, Third Military Medical University, Chongqing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Diao
authors.affiliation: Institute of Immunology, PLA, Third Military Medical University, Chongqing, China.
authors.forename: Xiaoyong
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, Yanbian University, Yanji, Jilin province, China.
authors.forename: Meihua
authors.initials: M
authors.lastname: Jin
authors.affiliation: Department of Basic Medicine, Yanbian University, Yanji, Jilin province, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department and Institute of Infectious Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Ning
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Lixin
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Institute of Immunology, PLA, Third Military Medical University, Chongqing, China.
authors.forename: Yuzhang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Institute of Immunology, PLA, Third Military Medical University, Chongqing, China.
authors.forename: Yongwen
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D018352:Coronavirus Infections / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D018450:Disease Progression; D005340:Fibrinogen / Q000378:metabolism; D054884:Host-Pathogen Interactions; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D053583:Interleukin-1beta / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006517:Murine hepatitis virus / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism; D053573:Receptors, Interleukin-1 Type I / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: D002352:Carrier Proteins; C490637:Fgl2 protein, mouse; C587672:IL1B protein, mouse; C583355:IL1R1 protein, mouse; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D053573:Receptors, Interleukin-1 Type I; D011994:Recombinant Proteins; D005340:Fibrinogen