title: Toll-like receptor 4 mediates alcohol-induced steatohepatitis through bone marrow-derived and endogenous liver cells in mice.
abstract: BACKGROUND
  Excessive alcohol intake causes an increase in intestinal permeability that induces translocation of gut-derived lipopolysaccharide (LPS) to the portal vein. Increased LPS in the portal vein stimulates Kupffer cells through Toll-like receptor (TLR) 4 in the liver. Activated TLR4 signaling in Kupffer cells induces various inflammatory mediators including TNF-α, IL-1β, and reactive oxygen species, resulting in liver injury. Hepatic stellate cells (HSCs) also express TLR4. This study investigates whether TLR4 on bone marrow (BM)-derived cells, including Kupffer cells, or non-BM-derived endogenous liver cells, including HSCs, contributes to the progression of alcohol-induced steatohepatitis and fibrogenesis in mice.
  
  
  METHODS
  TLR4 BM chimera (wild-type [WT] mice with TLR4(-/-) BM or TLR4(-/-) mice with WT BM) were generated by the combination of liposomal clodronate injection with whole body irradiation and BM transplantation, followed by treatment with intragastric alcohol feeding.
  
  
  RESULTS
  WT mice transplanted with WT BM exhibited liver injury, steatosis, inflammation, and a fibrogenic response. Conversely, TLR4(-/-) mice with TLR4(-/-) BM displayed less steatosis, liver injury, and inflammation. Notably, steatosis, macrophage infiltration, and alanine aminotransferase levels in both TLR4-chimeric mice showed intermediate levels between WT mice transplanted with WT BM and TLR4(-/-) mice transplanted with TLR4(-/-) BM. Hepatic mRNA expression of fibrogenic markers (collagen α1(I), TIMP1, TGF-β1) and inflammatory cytokines (IL-1β, IL-6) were markedly increased in WT mice with WT BM, but there was less of an increase in both TLR4-chimeric mice and in TLR4(-/-) mice transplanted with TLR4(-/-) BM.
  
  
  CONCLUSIONS
  TLR4 signaling in both BM-derived and non-BM-derived liver cells is required for liver steatosis, inflammation, and a fibrogenic response after chronic alcohol treatment.
authors.affiliation: Division of Gastroenterology, Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA 92093-0702, USA.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Inokuchi
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
authors.forename: EekJoong
authors.initials: E
authors.lastname: Park
authors.forename: Zhang-Xu
authors.initials: ZX
authors.lastname: Liu
authors.forename: David A
authors.initials: DA
authors.lastname: Brenner
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects* / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000097:blood / Q000633:toxicity; D016207:Cytokines / Q000096:biosynthesis; D000431:Ethanol / Q000097:blood / Q000633:toxicity; D005235:Fatty Liver, Alcoholic / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014280:Triglycerides / Q000032:analysis
chemical_list: D002492:Central Nervous System Depressants; D016207:Cytokines; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D014280:Triglycerides; D000431:Ethanol