Recent Insights into the Role of the Innate Immune System in the Development of Alcoholic Liver Disease

Abstract

The innate immune system is responsible for the rapid, initial response of the organism to potentially dangerous stresses, including pathogens, tissue injury, and malignancy. Pattern-recognition receptors of the toll-like receptor (TLR) family expressed by macrophages provide a first line of defense against microbial invasion. Activation of these receptors results in a stimulus-specific expression of genes required to control the infection, including the production of inflammatory cytokines and chemokines, followed by the recruitment of neutrophils to the site of infection. The early stages in the development of alcoholic liver disease (ALD) follow a pattern characteristic of an innate immune response. Kupffer cells, the resident macrophages in the liver, are activated in response to bacterial endotoxins (lipopolysaccharide, LPS), leading to the production of inflammatory and fibrogenic cytokines, reactive oxygen species, as well as the recruitment of neutrophils to the liver. One mechanism by which chronic ethanol can turn the highly regulated innate immune response into a pathway of disease is by disrupting the signal transduction cascades mediating the innate immune response. Recent studies have identified specific modules in the TLR-4 signaling cascade that are disrupted after chronic ethanol exposure, including CD14 and the mitogen-activated protein kinase family members, ERK1/2 and p38. Enhanced activation of these TLR-4 dependent signaling pathways after chronic ethanol likely contributes to the development of alcoholic liver disease.

Differential Contributions of C3, C5, and Decay-Accelerating Factor to Ethanol-Induced Fatty Liver in Mice

“…Previous studies have demonstrated a primary role for several components of the innate immune response, including Kupffer cells (36) and NKT cells (34) in the progression of ethanol-induced liver injury. Here we demonstrate that the complement pathway is intimately involved in the progression of ethanol-induced fatty liver .…”

Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice

“…The interaction of TLR-4 with endotoxin results in an activation of myeloid differentiation factor 88 (MyD88) and/or interferon regulatory factor 3 (IRF3) and subsequently through the activation of nuclear transcription factors to the release of numerous proinflammatory mediators such as TNF␣, which in turn can induce liver injury and fibrosis (for review, see Refs. 15,16). Recently, it was shown by Rivera et al 17 that TLR-4 mutant mice fed a methioninecholine-deficient diet are protected against nonalcoholic steatohepatitis.…”

The interleukin-17 pathway is involved in human alcoholic liver disease

“…The alcoholic fatty liver is sensitized to liver injury and displays increased TNF-␣ expression when stimulated by lipopolysaccharides or other toll-like receptor ligands. 9,10 This "two-hit" hypothesis of alcoholic-induced liver injury takes a major place in the current understanding of the pathogenesis of AH. 11,12 However, rodent experimental models of ALD do not exactly reproduce features of human AH, especially regarding chronic liver inflammatory infiltrates and fibrosis.…”