Abstract
Increasing evidence suggests that innate immunity plays an important role in alcohol-induced liver injury and most studies have focused on positive regulation of innate immunity. The main objective of this study was to investigate the negative regulator of innate immunity, IL-1/Toll-like receptor (TLR) signaling pathways and interleukin receptor-associated kinase-M (IRAK-M) in alcoholic liver injury. We established an alcohol-induced liver injury model using wild type and IRAK-M deficient B6 mice and investigated the possible mechanisms. We found that in the absence of IRAK-M, liver damage by alcohol was worse with higher alanine transaminase (ALT), more immune cell infiltration and increased numbers of IFNγ producing cells. We also found enhanced phagocytic activity in CD68+ cells. Moreover, our results revealed altered gut bacteria after alcohol consumption and this was more striking in the absence of IRAK-M. Our study provides evidence that IRAK-M plays an important role in alcohol-induced liver injury and IRAK-M negatively regulates the innate and possibly the adaptive immune response in the liver reacting to acute insult by alcohol. In the absence of IRAK-M, the hosts developed worse liver injury, enhanced gut permeability and altered gut microbiota.
Highlights
Alcoholic liver disease (ALD) comprises a spectrum of liver disorders that include alcoholic fatty liver, alcoholic steatohepatitis, liver cirrhosis and possibly hepatic carcinoma [1,2,3,4]
We found that there was a significant increase in IFNc producing CD8+ T cells in Liver mononuclear cells (LMNCs) of interleukin receptor-associated kinase (IRAK)-M2/2 mice after alcohol consumption compared to wild type (WT) B6 mice (Figure 4A and 4B)
interleukin receptor-associated kinase-M (IRAK-M) blocks the formation of MyD88/TRAF6 complex and inhibits downstream activation of NF-kB [9,11] and IRAK-M is an inhibitor of Toll-like receptor (TLR) signaling via MyD88
Summary
Alcoholic liver disease (ALD) comprises a spectrum of liver disorders that include alcoholic fatty liver, alcoholic steatohepatitis, liver cirrhosis and possibly hepatic carcinoma [1,2,3,4]. The pathogenesis of ALD is multi-factorial and affects different cell types in the liver with diverse consequences [5,6]. In addition to the direct effects of ethanol and its toxic metabolites on different cell types in the liver, increasing evidence suggests that innate immunity plays an important role in the pathogenesis of ALD [2,7,8]. IL-1/Toll-like receptor (TLR) signaling pathways and interleukin receptor-associated kinase (IRAK) family are critical molecules in innate immunity playing important roles in antipathogen responses, inflammation and autoimmunity [9,10]. Macrophages from IRAK-M deficient mice showed enhanced NF-kB activity and elevated expression of inflammatory cytokines upon stimulation with several TLR ligands [11,14,15]. IRAK-M2/2 mice had increased inflammatory responses to bacterial infection [11]
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