Wednesday, December 6, 2023
12/6/2023
PROJECT DESCRIPTION/SUMMARY 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 (MF) populations with a rapid loss of up to 50% of Kupffer cells and entry of infiltrating MFs. By 10 days Kupffer cell numbers are restored but they have become more anti-inflammatory. In mice lacking the initial burst of MF apoptosis, the shift to an anti-inflammatory phenotype at 10 days does not occur. The MF population changes correlate with changes in the sensitivity of the liver to a challenge with LPS and preliminary studies in both MF-MF and MF-hepatocyte co-cultures demonstrate that 10-day liver MFs 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 MFs 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 MFs 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 MFs 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 MF populations and use this information to identify similar MF populations in humans. We will use single cell RNA-seq and lineage tracing approaches to define the changing MF populations that follow alcohol exposure, characterize the different MF populations phenotypically, and identify MFs associated with alcohol adaptation in human liver tissue. Aim 2: To define the signals responsible for production and maintenance of anti-inflammatory, alcohol adaptive MF 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-MF interactions responsible for tolerance and injury. We will use micro-patterned hepatocyte-MF co-cultures to examine defined mixtures of hepatocytes and MFs to evaluate the different roles of MF subsets and hepatocytes in inflammatory sensitivity. These studies will enhance our knowledge of how MF phenotype changes protect the liver from alcohol and will provide fundamental support for the use of MF based therapies for alcoholic liver disease.
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