Journal
ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH
Volume 35, Issue 8, Pages 1509-1518Publisher
WILEY
DOI: 10.1111/j.1530-0277.2011.01487.x
Keywords
Innate Immunity; Lipopolysaccharide; Alcoholic Steatohepatitis; Alcoholic Liver Fibrosis
Categories
Funding
- NIAAA/NIH [AA11999]
- NIH [R01GM041804, R01AA020172, R01DK085252]
- American Association for the Study of Liver Diseases/American Liver Foundation
- ABMRF
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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-alpha, IL-1 beta, 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 alpha 1(I), TIMP1, TGF-beta 1) and inflammatory cytokines (IL-1 beta, 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.
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