title: Kupffer cells hasten resolution of liver immunopathology in mouse models of viral hepatitis.
abstract: Kupffer cells (KCs) are widely considered important contributors to liver injury during viral hepatitis due to their pro-inflammatory activity. Herein we utilized hepatitis B virus (HBV)-replication competent transgenic mice and wild-type mice infected with a hepatotropic adenovirus to demonstrate that KCs do not directly induce hepatocellular injury nor do they affect the pathogenic potential of virus-specific CD8 T cells. Instead, KCs limit the severity of liver immunopathology. Mechanistically, our results are most compatible with the hypothesis that KCs contain liver immunopathology by removing apoptotic hepatocytes in a manner largely dependent on scavenger receptors. Apoptotic hepatocytes not readily removed by KCs become secondarily necrotic and release high-mobility group box 1 (HMGB-1) protein, promoting organ infiltration by inflammatory cells, particularly neutrophils. Overall, these results indicate that KCs resolve rather than worsen liver immunopathology.
authors.affiliation: Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy. sitia.giovanni@hsr.it
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sitia
authors.forename: Matteo
authors.initials: M
authors.lastname: Iannacone
authors.forename: Roberto
authors.initials: R
authors.lastname: Aiolfi
authors.forename: Masanori
authors.initials: M
authors.lastname: Isogawa
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Cristina
authors.initials: C
authors.lastname: Scozzesi
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
authors.forename: Francis V
authors.initials: FV
authors.lastname: Chisari
authors.forename: Luca G
authors.initials: LG
authors.lastname: Guidotti
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D017209:Apoptosis; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D004002:Clodronic Acid / Q000008:administration & dosage / Q000494:pharmacology; D004195:Disease Models, Animal; D005682:Gadolinium / Q000494:pharmacology; D024002:HMGB Proteins / Q000097:blood / Q000378:metabolism; D006509:Hepatitis B / Q000276:immunology / Q000473:pathology* / Q000821:virology; D006515:Hepatitis B virus / Q000276:immunology / Q000502:physiology; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D008081:Liposomes; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D051116:Receptors, Scavenger / Q000378:metabolism; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D050071:Bone Density Conservation Agents; D024002:HMGB Proteins; D008081:Liposomes; D012333:RNA, Messenger; D051116:Receptors, Scavenger; D004002:Clodronic Acid; D005682:Gadolinium; C038958:gadolinium chloride