Acute alcoholic hepatitis (AH) is a severe inflammatory liver disease triggered by both chronic and binge drinking. The disease has a 30-day mortality of approximately 20%. One of the most striking features of AH is that it affects only a small minority of heavy drinkers suggesting that most individuals are protected from developing alcoholic liver inflammation by unknown mechanisms. We have shown that alcohol causes changes in mouse liver macrophage (M?) populations with a rapid loss of up to 50% of Kupffer cells and entry of infiltrating M?s. By 10 days Kupffer cell numbers are restored but they have become more anti-inflammatory. In mice lacking the initial burst of M? apoptosis, the shift to an anti-inflammatory phenotype at 10 days does not occur. The M? population changes correlate with changes in the sensitivity of the liver to a challenge with LPS and preliminary studies in both M?-M? and M?-hepatocyte co-cultures demonstrate that 10-day liver M?s can suppress LPS-induced inflammatory responses. We hypothesize that exposure to alcohol causes dynamic and adaptive changes in both Kupffer cells and non-Kupffer cell infiltrating M?s and when this adaptation is successful it leads to an adaptive state in which liver inflammation is minimal. Adaptation requires Kupffer cell-derived apoptotic bodies and Th2 cytokines such as IL4 and IL13. The balance of pro-and anti-inflammatory M?s and the sensitivity of hepatocytes to pro-inflammatory cytokines change over time so that with prolonged alcohol exposure, adaptation can be lost and liver inflammation can occur. Better understanding of the identity and function of adaptive M?s will allow us to identify similar cells in humans. Understanding the factors that lead to their formation and maintenance would provide new approaches for the therapy of alcoholic liver disease. We will explore this hypothesis with the following specific aims:
Aim 1 : To examine alcohol-induced adaptive changes in mouse liver M? populations and use this information to identify similar M? populations in humans. We will use single cell RNA-seq and lineage tracing approaches to define the changing M? populations that follow alcohol exposure, characterize the different M? populations phenotypically, and identify M?s associated with alcohol adaptation in human liver tissue.
Aim 2 : To define the signals responsible for production and maintenance of anti-inflammatory, alcohol adaptive M? populations in mice. We will examine the role of apoptotic body receptors and hepatocyte derived factors including Th2 cytokines.
Aim 3 : To examine the hepatocyte-M? interactions responsible for tolerance and injury. We will use micro-patterned hepatocyte-M? co-cultures to examine defined mixtures of hepatocytes and M?s to evaluate the different roles of M? subsets and hepatocytes in inflammatory sensitivity. These studies will enhance our knowledge of how M? phenotype changes protect the liver from alcohol and will provide fundamental support for the use of M? based therapies for alcoholic liver disease.

Public Health Relevance

Alcoholic hepatitis is a severe acute liver disease with significant 30-day mortality but most heavy drinkers do not develop liver disease. This project will examine the hypothesis that adaptive changes in liver macrophages normally protect the liver from inflammation due to alcohol. It will determine the factors necessary to form protective macrophages and evaluate how these can be used for prevention and treatment.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Wang, Joe
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University of Kansas
Internal Medicine/Medicine
Schools of Medicine
Kansas City
United States
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