The role of neutrophils in alcohol-related hepatitis

Alcohol-related liver disease (ALD) is a major cause of liver disease associated mortality, with inpatient care being a major contributor to clinical and economic burden. Alcohol-related hepatitis (AH) is an acute inflammatory form of ALD. Severe AH is associated with a high short-term mortality, with infection being a common cause of death. The presence of AH is associated with increased numbers of circulating and hepatic neutrophils. We review the literature on the role of neutrophils in alcoholic hepatitis. In particular, we explain how neutrophils are recruited to the inflamed liver, and how their antimicrobial functions (chemotaxis, phagocytosis, oxidative burst, NETosis) may be altered in AH. We highlight evidence for the existence of ‘high-density’ and ‘low-density’ neutrophil subsets. We also describe the potentially beneficial roles of neutrophils in resolution of injury in AH through their effects on macrophage polarisation, and hepatic regeneration. Finally, we discuss how manipulation of neutrophil recruitment/function may be used as a therapeutic strategy in AH. For example, correction of gut dysbiosis in AH could help to prevent excess neutrophil activation, or treatments could aim to enhance miR-223 function in AH. The development of markers that can reliably distinguish neutrophil subsets, and the development of animal models that accurately reproduce human disease are important areas for facilitating translation of research in this important field. Alcohol-related liver disease (ALD) is a major cause of liver disease associated mortality, with inpatient care being a major contributor to clinical and economic burden. Alcohol-related hepatitis (AH) is an acute inflammatory form of ALD. Severe AH is associated with a high short-term mortality, with infection being a common cause of death. The presence of AH is associated with increased numbers of circulating and hepatic neutrophils. We review the literature on the role of neutrophils in alcoholic hepatitis. In particular, we explain how neutrophils are recruited to the inflamed liver, and how their antimicrobial functions (chemotaxis, phagocytosis, oxidative burst, NETosis) may be altered in AH. We highlight evidence for the existence of ‘high-density’ and ‘low-density’ neutrophil subsets. We also describe the potentially beneficial roles of neutrophils in resolution of injury in AH through their effects on macrophage polarisation, and hepatic regeneration. Finally, we discuss how manipulation of neutrophil recruitment/function may be used as a therapeutic strategy in AH. For example, correction of gut dysbiosis in AH could help to prevent excess neutrophil activation, or treatments could aim to enhance miR-223 function in AH. The development of markers that can reliably distinguish neutrophil subsets, and the development of animal models that accurately reproduce human disease are important areas for facilitating translation of research in this important field. Nil to disclose. PNN and PFL are supported by the NIHR Birmingham Biomedical Research Centre based at University Hospitals Birmingham and the University of Birmingham. RK is supported by a Medical Research Council Clinical Research Training Fellowship grant. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. PNN and RK had the original concept. RK wrote the first draft of the manuscript and all authors reviewed the final version. PNN is guarantor. Key points:•Alcohol-related hepatitis (AH) is frequently associated with increased neutrophil counts in the circulation and in the liver.•Neutrophils in AH are activated at baseline, predisposing them to spontaneous NETosis, release of reactive oxygen species and proteases.•Neutrophils in AH have impaired phagocytosis and oxidative burst responses to E coli, which may increase infection risk.•Neutrophils may contribute to resolution of injury through release of hepatocyte growth factor and inducing conversion of macrophages to a ‘pro-resolution’ phenotype.•Neutrophil mir-223 protects against oxidative stress, but its expression is reduced in AH. •Alcohol-related hepatitis (AH) is frequently associated with increased neutrophil counts in the circulation and in the liver.•Neutrophils in AH are activated at baseline, predisposing them to spontaneous NETosis, release of reactive oxygen species and proteases.•Neutrophils in AH have impaired phagocytosis and oxidative burst responses to E coli, which may increase infection risk.•Neutrophils may contribute to resolution of injury through release of hepatocyte growth factor and inducing conversion of macrophages to a ‘pro-resolution’ phenotype.•Neutrophil mir-223 protects against oxidative stress, but its expression is reduced in AH.