Neutrophil extracellular traps (NETs) and NETosis in alcohol-associated diseases: A systematic review

Heavy alcohol consumption is implicated in the alteration of the antimicrobial function of neutrophils, such as phagocytosis, chemotaxis, the formation of neutrophil extracellular traps (NETs), and the occurrence of NETosis. NETosis is an endogenous process of elimination of invading microbes, autoantibodies, and inflammatory elements such as danger-associated molecular patterns (DAMPs) and pathogen-associated patterns (PAMPs). However, both exaggeration and suppression of NETosis modulate normal physiological and metabolic processes by influencing events at the molecular and cellular levels. Recent research shows that binge alcohol consumption induces NETosis, leading to tissue damage and inflammation. Binge alcohol consumption, chronic alcohol intake, and alcohol use disorder (AUD) can affect immunity and often lead to alcohol-associated liver disease (ALD) and/or other organ damage. Alcohol can lead to detrimental consequences in multiple organs, including the brain, liver, pancreas, and gut. Gut-derived microbial substances, such as endotoxins in the circulation, induce systemic inflammation. Sterile danger signals from damaged cells, cytokines, and prostaglandins act as proinflammatory stimuli and are involved in multiple signaling pathways. The alcohol-induced proinflammatory cytokines chemoattract neutrophils, which interact and coordinate with other immune cells to exaggerate or suppress inflammation within the inflammatory milieu, depending on the alcohol effects. Several proteins, including different receptors, play important roles in the activation and formation of NETs as well as the initiation and execution of NETosis. This review article specifically gathers the current information on NETosis, its biological components, and signaling pathways relating to the formation of NETs and the occurrence of NETosis associated with ALD and AUD in multiorgans, specifically in the brain, liver, and gut. We also briefly describe various therapeutic strategies against AUD-associated NETosis in experimental models and human disease states.