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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Anti-Inflammatory Agents / pharmacology
-
Apoptosis
-
Bone Density Conservation Agents / administration & dosage
-
Bone Density Conservation Agents / pharmacology
-
CD8-Positive T-Lymphocytes / metabolism
-
Clodronic Acid / administration & dosage
-
Clodronic Acid / pharmacology
-
Disease Models, Animal
-
Gadolinium / pharmacology
-
HMGB Proteins / blood
-
HMGB Proteins / metabolism
-
Hepatitis B / immunology
-
Hepatitis B / pathology*
-
Hepatitis B / virology
-
Hepatitis B virus / immunology
-
Hepatitis B virus / physiology
-
Hepatocytes / immunology
-
Hepatocytes / metabolism*
-
Hepatocytes / pathology
-
Kupffer Cells / drug effects
-
Kupffer Cells / immunology
-
Kupffer Cells / physiology*
-
Liposomes
-
Liver / immunology
-
Liver / metabolism
-
Liver / pathology*
-
Liver / virology
-
Male
-
Mice
-
Mice, Inbred C57BL
-
Mice, Transgenic
-
Neutrophils / physiology
-
RNA, Messenger / genetics
-
Receptors, Scavenger / metabolism
-
Time Factors
Substances
-
Anti-Inflammatory Agents
-
Bone Density Conservation Agents
-
HMGB Proteins
-
Liposomes
-
RNA, Messenger
-
Receptors, Scavenger
-
Clodronic Acid
-
Gadolinium
-
gadolinium chloride