title: TLR4-Dependent Secretion by Hepatic Stellate Cells of the Neutrophil-Chemoattractant CXCL1 Mediates Liver Response to Gut Microbiota.
abstract: OBJECTIVE
  The gut microbiota significantly influences hepatic immunity. Little is known on the precise mechanism by which liver cells mediate recognition of gut microbes at steady state. Here we tested the hypothesis that a specific liver cell population was the sensor and we aimed at deciphering the mechanism by which the activation of TLR4 pathway would mediate liver response to gut microbiota.
  
  
  METHODS
  Using microarrays, we compared total liver gene expression in WT versus TLR4 deficient mice. We performed in situ localization of the major candidate protein, CXCL1. With an innovative technique based on cell sorting, we harvested enriched fractions of KCs, LSECs and HSCs from the same liver. The cytokine secretion profile was quantified in response to low levels of LPS (1ng/mL). Chemotactic activity of stellate cell-derived CXCL1 was assayed in vitro on neutrophils upon TLR4 activation.
  
  
  RESULTS
  TLR4 deficient liver had reduced levels of one unique chemokine, CXCL1 and subsequent decreased of neutrophil counts. Depletion of gut microbiota mimicked TLR4 deficient phenotype, i.e., decreased neutrophils counts in the liver. All liver cells were responsive to low levels of LPS, but hepatic stellate cells were the major source of chemotactic levels of CXCL1. Neutrophil migration towards secretory hepatic stellate cells required the TLR4 dependent secretion of CXCL1.
  
  
  CONCLUSIONS
  Showing the specific activation of TLR4 and the secretion of one major functional chemokine-CXCL1, the homolog of human IL-8-, we elucidate a new mechanism in which Hepatic Stellate Cells play a central role in the recognition of gut microbes by the liver at steady state.
authors.affiliation: Seattle Biomedical Research Institute, 307 North Westlake Avenue, Seattle, Washington, 98109-5219, United States of America.
authors.forename: Amélie E
authors.initials: AE
authors.lastname: Bigorgne
authors.affiliation: Seattle Biomedical Research Institute, 307 North Westlake Avenue, Seattle, Washington, 98109-5219, United States of America.
authors.forename: Beena
authors.initials: B
authors.lastname: John
authors.affiliation: Seattle Biomedical Research Institute, 307 North Westlake Avenue, Seattle, Washington, 98109-5219, United States of America.
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Ebrahimkhani
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, 98195-7470, United States of America.
authors.forename: Masami
authors.initials: M
authors.lastname: Shimizu-Albergine
authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, 98195-7470, United States of America.
authors.forename: Jean S
authors.initials: JS
authors.lastname: Campbell
authors.affiliation: Seattle Biomedical Research Institute, 307 North Westlake Avenue, Seattle, Washington, 98109-5219, United States of America.|Department of Pathology, University of Washington, Seattle, Washington, 98195-7470, United States of America.
authors.forename: Ian N
authors.initials: IN
authors.lastname: Crispe
mesh_terms: D000818:Animals; D054360:Chemokine CXCL1 / Q000276:immunology*; D000069196:Gastrointestinal Microbiome / Q000276:immunology*; D055166:Hepatic Stellate Cells / Q000276:immunology*; D016209:Interleukin-8 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D016209:Interleukin-8; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4