title: 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.
abstract: 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-β, and lower tumor necrosis factor alpha (TNF-α) 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Petrasek
authors.forename: Angela
authors.initials: A
authors.lastname: Dolganiuc
authors.forename: Timea
authors.initials: T
authors.lastname: Csak
authors.forename: Bharath
authors.initials: B
authors.lastname: Nath
authors.forename: Istvan
authors.initials: I
authors.lastname: Hritz
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.forename: Donna
authors.initials: D
authors.lastname: Catalano
authors.forename: Evelyn
authors.initials: E
authors.lastname: Kurt-Jones
authors.forename: Pranoti
authors.initials: P
authors.lastname: Mandrekar
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D000431:Ethanol / Q000009:adverse effects*; D005260:Female; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D007370:Interferon Type I / Q000378:metabolism*; D016753:Interleukin-10 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D016207:Cytokines; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D051193:Toll-Like Receptors; D016753:Interleukin-10; D000431:Ethanol