title: Liver fibrosis occurs through dysregulation of MyD88-dependent innate B-cell activity.
abstract: Chronic liver disease mediated by activation of hepatic stellate cells (HSCs) leads to liver fibrosis. Here, we postulated that the immune regulatory properties of HSCs might promote the profibrogenic activity of B cells. Fibrosis is completely attenuated in carbon tetrachloride-treated, B cell-deficient µMT mice, showing that B cells are required. The retinoic acid produced by HSCs augmented B-cell survival, plasma cell marker CD138 expression, and immunoglobulin G production. These activities were reversed following addition of the retinoic acid inhibitor LE540. Transcriptional profiling of fibrotic liver B cells revealed increased expression of genes related to activation of nuclear factor κ light chain enhancer of activated B cells, proinflammatory cytokine production, and CD40 signaling, suggesting that these B cells are activated and may be acting as inflammatory cells. Biological validation experiments also revealed increased activation (CD44 and CD86 expression), constitutive immunoglobulin G production, and secretion of the proinflammatory cytokines tumor necrosis factor-α, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1α. Likewise, targeted deletion of B-cell-intrinsic myeloid differentiation primary response gene 88 signaling, an innate adaptor with involvement in retinoic acid signaling, resulted in reduced infiltration of migratory CD11c(+) dendritic cells and Ly6C(++) monocytes and, hence, reduced liver pathology.
  
  
  CONCLUSIONS
  Liver fibrosis occurs through a mechanism of HSC-mediated augmentation of innate B-cell activity. These findings highlight B cells as important "first responders" of the intrahepatic immune environment.
authors.affiliation: Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA.
authors.forename: Manoj
authors.initials: M
authors.lastname: Thapa
authors.affiliation: Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA.
authors.forename: Raghavan
authors.initials: R
authors.lastname: Chinnadurai
authors.affiliation: Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Velazquez
authors.affiliation: Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA.
authors.forename: Dana
authors.initials: D
authors.lastname: Tedesco
authors.affiliation: Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Elrod
authors.affiliation: Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA.
authors.forename: Jin-Hwan
authors.initials: JH
authors.lastname: Han
authors.affiliation: Division of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA.
authors.forename: Prachi
authors.initials: P
authors.lastname: Sharma
authors.affiliation: Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA.
authors.forename: Chris
authors.initials: C
authors.lastname: Ibegbu
authors.affiliation: Department of Biology, Georgia State University, Atlanta, GA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Gewirtz
authors.affiliation: Division of Digestive Diseases, Emory University School of Medicine, Atlanta, GA.
authors.forename: Frank
authors.initials: F
authors.lastname: Anania
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA.
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran
authors.affiliation: Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA.|Department of Pediatrics and Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA.
authors.forename: Mehul S
authors.initials: MS
authors.lastname: Suthar
authors.affiliation: Emory Vaccine Center, Division of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA.|Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA.
authors.forename: Arash
authors.initials: A
authors.lastname: Grakoui
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000502:physiology*; D002454:Cell Differentiation; D020869:Gene Expression Profiling; D055166:Hepatic Stellate Cells / Q000502:physiology*; D008103:Liver Cirrhosis / Q000276:immunology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D014212:Tretinoin / Q000502:physiology*
chemical_list: C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D014212:Tretinoin