Academic journal article Alcohol Research

The Role of Innate Immunity in Alcoholic Liver Disease

Academic journal article Alcohol Research

The Role of Innate Immunity in Alcoholic Liver Disease

Article excerpt

Heavy consumption of alcohol poses a well-known health risk worldwide. Alcohol's effects on health and well-being are numerous and include injuries and fatalities resulting from alcohol-induced incapacitation. Moreover, chronic and heavy alcohol consumption affects the integrity and function of vital tissues and organs, causing slow but significant structural and functional damage over time. One of alcohol's principal actions is damage to the liver, the primary organ for its metabolism. As a result, some 90 percent of heavy drinkers (i.e., those drinking 60 g or more of alcohol per day)-and even some who drink less- develop fatty liver (i.e., steatosis) (O'Shea et al. 2009). Up to one-third of heavy drinkers may incur more extensive liver injury, including alcoholic hepatitis, scarring (i.e., fibrosis), cirrhosis, or liver cancer (Gao et al. 2011). Moreover, about 70 percent of individuals who develop alcoholic hepatitis will progress to cirrhosis (Schwartz and Reinus 2012). The spectrum of alcohol-induced liver injuries ranging from steatosis to cirrhosis, defined here as alcoholic liver disease (ALD), is therefore a major cause of liver impairment worldwide (Gao et al. 2011).

A major contributor to ALD is alcohol-induced activation of liver innate immunity, precipitating disorders ranging from localized and transient inflammation to widespread hepatocellular injury and tissue damage (Cohen and Nagy 2011; Gao et al. 2011; Orman et al. 2013; Seki and Schnabl 2012; Wang et al. 2012). Given the pivotal role of the innate immune system in protecting the liver against foreign agents, it may seem surprising that some of the worst outcomes of alcohol-induced liver disease are the result of activation of innate immune cells. But, in fact, recent studies have revealed that alcohol induces immune activation, which drives the progression of ALD.

Innate immunity comprises chemical-physical barriers (e.g., epidermal cells, mucous membranes, and pH), as well as cellular defenses against any invading microbe or agent the immune system perceives as dangerous to the body's cells and tissues (Gao et al. 2011). These cellular defenses, which include both immune cells (e.g., macrophages and dendritic cells) and proteins (e.g., cytokines), normally are well balanced to sense and respond to harmful agents while avoiding unnecessary immune activation. Alcohol disrupts this balance, triggering immune responses that result in inflammation (Gao et al. 2011; Seki and Schnabl 2012; Szabo et al. 2011; Wang et al. 2012). Continued high alcohol intake fuels a multistage process in which alcohol-induced liver damage advances along a continuum of steatosis, inflammation, and fibrosis, to the final stage, cirrhosis, marked by widespread tissue deformation and damage (Gao et al. 2011; Orman et al. 2013; Seki and Schnabl 2012; Wang et al. 2012).

It has been known for some time that alcohol consumption triggers inflammation of the liver, but how alcohol brings about this disease state has long remained unclear. More recently, researchers have uncovered key roles of Toll-like receptors (TLRs), whose activation during alcohol exposure results in upregulation of pro-inflammatory cytokines (e.g., tumor necrosis factor a [TNFa] and interleukin [IL]-1β) and chemokines (e.g., monocyte chemoattractant protein [MCP]-1). Moreover, these immune responses result in production of reactive oxygen species (ROS), epigenetic changes, and infiltration of tissues with circulating monocytes and neutrophils (Gao et al. 2011; Petrasek et al. 2013; Seki and Schnabl 2012; Szabo et al. 2011; Wang et al. 2012).

Although the exact molecular mechanisms through which alcohol activates innate immune cells are not entirely understood, there is increasing evidence for the close relationship between the effects of alcohol on the gastrointestinal (GI) tract and injury to the liver. Heavy alcohol consumption changes the composition of microbial communities in the GI system, tipping the balance toward more pathogenic species. …

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