Interferon regulatory factor 3 and type I interferons are protective in alcoholic liver injury in mice by way of crosstalk of parenchymal and myeloid cells
Department of Medicine, Division of Gastroenterology; Department of Medicine, Division of Infectious Diseases and Immunology
Medical Subject Headings
Liver Diseases, Alcoholic; Immunity, Innate; Interferon Type I; Interferon Regulatory Factor-3
Alcoholic liver disease (ALD) features increased hepatic exposure to bacterial lipopolysaccharide (LPS). Toll-like receptor-4 (TLR4) recognizes LPS and activates signaling pathways depending on MyD88 or TRIF adaptors. We previously showed that MyD88 is dispensable in ALD. TLR4 induces Type I interferons (IFNs) in an MyD88-independent manner that involves interferon regulatory factor-3 (IRF3). We fed alcohol or control diets to wild-type (WT) and IRF3 knock-out (KO) mice, and to mice with selective IRF3 deficiency in liver parenchymal and bone marrow-derived cells. Whole-body IRF3-KO mice were protected from alcohol-induced liver injury, steatosis, and inflammation. In contrast to WT or bone marrow-specific IRF3-KO mice, deficiency of IRF3 only in parenchymal cells aggravated alcohol-induced liver injury, associated with increased proinflammatory cytokines, lower antiinflammatory cytokine interleukin 10 (IL-10), and lower Type I IFNs compared to WT mice. Coculture of WT primary murine hepatocytes with liver mononuclear cells (LMNC) resulted in higher LPS-induced IL-10 and IFN-beta, and lower tumor necrosis factor alpha (TNF-alpha) levels compared to LMNC alone. Type I IFN was important because cocultures of hepatocytes with LMNC from Type I IFN receptor KO mice showed attenuated IL-10 levels compared to control cocultures from WT mice. We further identified that Type I IFNs potentiated LPS-induced IL-10 and inhibited inflammatory cytokine production in both murine macrophages and human leukocytes, indicating preserved cross-species effects. These findings suggest that liver parenchymal cells are the dominant source of Type I IFN in a TLR4/IRF3-dependent manner. Further, parenchymal cell-derived Type I IFNs increase antiinflammatory and suppress proinflammatory cytokines production by LMNC in paracrine manner. Conclusion: Our results indicate that IRF3 activation in parenchymal cells and resulting type I IFNs have protective effects in ALD by way of modulation of inflammatory functions in macrophages. These results suggest potential therapeutic targets in ALD. (HEPATOLOGY 2011;53:649-660.).
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Citation: Petrasek, J., Dolganiuc, A., Csak, T., Nath, B., Hritz, I., Kodys, K., Catalano, D., Kurt-Jones, E., Mandrekar, P. and Szabo, G. (2011), Interferon regulatory factor 3 and type I interferons are protective in alcoholic liver injury in mice by way of crosstalk of parenchymal and myeloid cells . Hepatology, 53: 649–660. doi: 10.1002/hep.24059. Link to article on publisher's site
Petrasek, Jan; Dolganiuc, Angela; Csak, Timea; Nath, Bharath D.; Hritz, Istvan; Kodys, Karen; Catalano, Donna; Kurt-Jones, Evelyn A.; Mandrekar, Pranoti; and Szabo, Gyongyi, "Interferon regulatory factor 3 and type I interferons are protective in alcoholic liver injury in mice by way of crosstalk of parenchymal and myeloid cells" (2011). Gastroenterology Publications and Presentations. 96.