http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.1002061
Kupffer Cells Hasten Resolution of Liver Immunopathology in Mouse Models of Viral HepatitisGiovanni Sitia1#*, Matteo Iannacone1,2#*, Roberto Aiolfi1, Masanori Isogawa3, Nico van Rooijen4, Cristina Scozzesi5, Marco E. Bianchi6,7, Ulrich H. von Andrian2, Francis V. Chisari3, Luca G. Guidotti1,3* 1 Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy, 2 Immune Disease Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America, 3 Department of Immunology & Microbial Sciences, The Scripps Research Institute, La Jolla, California, United States of America, 4 Department of Molecular Cell Biology, Free University Medical Center, Amsterdam, The Netherlands, 5 DiaPro Diagnostic Bioprobes, Milan, Italy, 6 Vita-Salute San Raffaele University, Milan, Italy, 7 Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy Abstract TopKupffer 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.
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