title: IL-1β production through the NLRP3 inflammasome by hepatic macrophages links hepatitis C virus infection with liver inflammation and disease.
abstract: Chronic hepatitis C virus (HCV) infection is a leading cause of liver disease. Liver inflammation underlies infection-induced fibrosis, cirrhosis and liver cancer but the processes that promote hepatic inflammation by HCV are not defined. We provide a systems biology analysis with multiple lines of evidence to indicate that interleukin-1β (IL-1β) production by intrahepatic macrophages confers liver inflammation through HCV-induced inflammasome signaling. Chronic hepatitis C patients exhibited elevated levels of serum IL-1β compared to healthy controls. Immunohistochemical analysis of healthy control and chronic hepatitis C liver sections revealed that Kupffer cells, resident hepatic macrophages, are the primary cellular source of hepatic IL-1β during HCV infection. Accordingly, we found that both blood monocyte-derived primary human macrophages, and Kupffer cells recovered from normal donor liver, produce IL-1β after HCV exposure. Using the THP-1 macrophage cell-culture model, we found that HCV drives a rapid but transient caspase-1 activation to stimulate IL-1β secretion. HCV can enter macrophages through non-CD81 mediated phagocytic uptake that is independent of productive infection. Viral RNA triggers MyD88-mediated TLR7 signaling to induce IL-1β mRNA expression. HCV uptake concomitantly induces a potassium efflux that activates the NLRP3 inflammasome for IL-1β processing and secretion. RNA sequencing analysis comparing THP1 cells and chronic hepatitis C patient liver demonstrates that viral engagement of the NLRP3 inflammasome stimulates IL-1β production to drive proinflammatory cytokine, chemokine, and immune-regulatory gene expression networks linked with HCV disease severity. These studies identify intrahepatic IL-1β production as a central feature of liver inflammation during HCV infection. Thus, strategies to suppress NLRP3 or IL-1β activity could offer therapeutic actions to reduce hepatic inflammation and mitigate disease.
authors: Center for the Study of Hepatitis C Virus Infection and Immunity, Department of Immunology, University of Washington, Seattle, Washington, USA.
authors: Amina A
authors: AA
authors: Negash
authors: Hilario J
authors: HJ
authors: Ramos
authors: Nanette
authors: N
authors: Crochet
authors: Daryl T Y
authors: DT
authors: Lau
authors: Brian
authors: B
authors: Doehle
authors: Neven
authors: N
authors: Papic
authors: Don A
authors: DA
authors: Delker
authors: Juandy
authors: J
authors: Jo
authors: Antonio
authors: A
authors: Bertoletti
authors: Curt H
authors: CH
authors: Hagedorn
authors: Michael
authors: M
authors: Gale
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D002460:Cell Line; D018925:Chemokines / Q000096:biosynthesis; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation; D016174:Hepacivirus / Q000276:immunology; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008107:Liver Diseases / Q000276:immunology / Q000821:virology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010587:Phagocytosis; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D060225:Tetraspanin 28; D051199:Toll-Like Receptor 7 / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D018925:Chemokines; D016207:Cytokines; D058847:Inflammasomes; D053583:Interleukin-1beta; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D012333:RNA, Messenger; C495348:TLR7 protein, human; D060225:Tetraspanin 28; D051199:Toll-Like Receptor 7; D020170:Caspase 1
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