Innate lymphocytes: Role in alcohol-induced immune dysfunction

Abstract

Alcohol use is known to alter the function of both innate and adaptive immune cells, such as neutrophils, macrophages, B cells, and T cells. Immune dysfunction has been associated with alcohol-induced end-organ damage. The role of innate lymphocytes in alcohol-associated pathogenesis has become a focus of research, as liver-resident natural killer (NK) cells were found to play an important role in alcohol-associated liver damage pathogenesis. Innate lymphocytes play a critical role in immunity and homeostasis; they are necessary for an optimal host response against insults including infections and cancer. However, the role of innate lymphocytes, including NK cells, natural killer T (NKT) cells, mucosal associated invariant T (MAIT) cells, gamma delta T cells, and innate lymphoid cells (ILCs) type 1-3, remains ill-defined in the context of alcohol-induced end-organ damage. Innate-like B lymphocytes including marginal zone B cells and B-1 cells have also been identified; however, this review will address the effects of alcohol misuse on innate T lymphocytes, as well as the consequences of innate T-lymphocyte dysfunction on alcohol-induced tissue damage.

Keywords: alcohol; bacteria; innate immunity; innate lymphocytes; pneumonia.

Figure 1

An overview of innate and innate-like immune cells examined in this review.

Figure 2

Examples of alcohol related organ injury with potential influences from the innate-like immune system. Many tissues rely on processes regulated by innate-like immune signaling to maintain homeostasis. Alcohol can perturb homeostasis by interfering with signal release (ex. decrease in IL-22 release by ILC-3 cells), by depleting or activating regulatory cells (ex. maturation of iNKT and inactivation of NK cells following alcohol exposure) or by interfering with effector cell function. Little has been rigorously established about how broad changes in the innate-like immune system result in tissue damage. However, we can make some informed inferences. Depletion of signals like IL-22 could facilitate injury in tissues like the lungs and small intestines (2, 5) because IL-22 is a fundamental mediator of inflammation, mucous production and tissue regeneration. During necrotic alcohol-associated tissue injuries (3, 4), there is often tissue infiltration by cytolytic elements including NK cells. In a healthy individual, the activity of these cytotoxic elements is kept in check by cytokine signaling by innate-like including iNKT cells. However, alcohol exposure can dysregulate this signaling and periods of hypo- and hyperactive cytolytic activity may result.

Figure 3

The interplay between iNKT cells and NK cells appears central to the pathogenesis of hepatic steatosis and other aspects of alcoholic liver disease. Mature NK cells appear to oppose hepatic steatosis, but also facilitate tissue injury through cytotoxic activity (1). Acutely, NK activity is thought to be beneficial; NK cells release IFN-γ which downregulates a variety of lipogenic and fatty uptake genes (2). NK cells can also promote beneficial remodeling and regeneration of the liver. Chronically however, over activation of NK cells may contribute to liver injury (3). Alcohol can perturb the iNKT/NK cell balance, favoring iNKT cell maturation while suppressing the maturation of NK cells (3). This change can be achieved through a variety of possible mechanisms. For example, ethanol impairs the release of IL-15 which promotes the maturation of NK cells (4). Ethanol can also promote the release of IL-10 from iNKT cells which will suppress NK activity (5).