Academic journal article Alcohol Research: Current Reviews

The Role of Innate Immunity in Alcoholic Liver Disease

Academic journal article Alcohol Research: Current Reviews

The Role of Innate Immunity in Alcoholic Liver Disease

Article excerpt

The innate immune system represents the first-line response to invading microbes, tissue damage, or aberrant cell growth. Many of the proteins and cells involved in innate immunity are produced by, and reside in, the liver. This abundance in immune cells and proteins reflects the liver's adaptation to various immune challenges but also makes the organ particularly vulnerable to alcohol's effects. Heavy alcohol consumption may produce leakage of microbes and microbial products from the gastrointestinal tract, which quickly reach the liver via the portal vein. Exposure to these immune challenges and to alcohol and its breakdown products dysregulates the liver's normally fine-tuned immune signaling pathways, leading to activation of various cellular sensors of pathogen- or damage-associated molecular patterns. The ensuing expression of pro-inflammatory cytokines (e.g., tumor necrosis factor a [TNF[alpha]], interleukin [IL]-8, and IL-1[beta]) results in cellular dysfunction that contributes to alcoholic liver disease (ALD). Investigations into the roles of the various components of liver innate immunity in ALD have begun to uncover the molecular basis of this disease. Further progress in this area may help inform the development of interventions targeting the innate system to augment current treatments of ALD. These treatments could include antibodies against pro-inflammatory cytokines, use of anti-inflammatory cytokines, or suppression of alcohol-induced epigenetic regulators of innate immunity.

Key words: Alcohol use, abuse and dependence; heavy alcohol drinking; alcohol effects and consequences; alcoholic liver disease; liver; gastrointestinal tract; immunity; innate immune system; immune cells; cytokines; chemokines; inflammation

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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. …

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