Toll-Like Receptor 4 Mediates Alcohol-Induced Steatohepatitis Through Bone Marrow-Derived and Endogenous Liver Cells in Mice
Article first published online: 4 APR 2011
Copyright © 2011 by the Research Society on Alcoholism
Alcoholism: Clinical and Experimental Research
Volume 35, Issue 8, pages 1509–1518, August 2011
How to Cite
Inokuchi, S., Tsukamoto, H., Park, E., Liu, Z.-X., Brenner, D. A. and Seki, E. (2011), Toll-Like Receptor 4 Mediates Alcohol-Induced Steatohepatitis Through Bone Marrow-Derived and Endogenous Liver Cells in Mice. Alcoholism: Clinical and Experimental Research, 35: 1509–1518. doi: 10.1111/j.1530-0277.2011.01487.x
- Issue published online: 22 JUL 2011
- Article first published online: 4 APR 2011
- Received for publication August 23, 2010; accepted January 4, 2011.
- Innate Immunity;
- Alcoholic Steatohepatitis;
- Alcoholic Liver Fibrosis
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.