Role of gp91phox in Hepatic MF Programming and Alcohol Liver Disease

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 DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) affects more than 10 million people in the U.S. and accounts for nearly half of liver cirrhosis-associated deaths. A better understanding of the pathogenesis of the disease is necessary to develop new therapies, which are currently quite limited. The innate immune system plays an important role in the pathogenesis of ALD. Macrophages (MΦ) is a major type of cells of the innate immunity, and has emerged as a critical player and therapeutic target in many chronic inflammatory diseases. Evidence suggests that hepatic MΦ s are important in the development and progression of ALD. In patients and animal models, increased numbers of hepatic MΦ are found in all stages of ALD, and factors indicating MΦ activation are elevated. Hepatic MΦ s are a heterogeneous population with diverse phenotype and functions. Aside from resident Kupffer cells (KCs), we recently discovered that chronic ethanol feeding to mice causes the hepatic recruitment of infiltrating MΦ s (IMs), which consist of a pro-inflammatory Ly6Chi subset and an anti- inflammatory, tissue-protective Ly6Clow subset. Phagocytosis of dead cells (efferocytosis) promotes the switching of Ly6Chi IMs to Ly6Clow IMs. Moreover, we found that hepatic MΦ s from gp91phox-/- mice have impaired efferocytosis ability. Interestingly, compared with ethanol-fed WT mice, the ratio of Ly6Chi/Ly6Clow IMs, as well as the degree of liver injury, are significantly higher in gp91phox-/- mice. These results led to our hypothesis that gp91phox, through regulating MΦ efferocytosis, plays a critical role in the programming of tissue- restorative hepatic MΦ s, thereby protecting the liver from ALD. We propose two Specific Aims to examine this hypothesis: (Aim 1), Investigate the protective role of gp91phox in ethanol-induced liver inflammation and injury. The degrees of liver injury and inflammation will be compared between WT and gp91phox-/- mice in two models of ALD. Furthermore, bone marrow chimera experiments will be performed to elucidate the contribution of hepatic MΦs to the increased susceptibility of gp91phox-/- mice to ALD. (Aim 2), Investigate the impact of gp91phox-deletion on efferocytosis-induced programming of hepatic MΦs. Various subpopulations of MΦs will be isolated from the livers of ethanol-fed WT and gp91phox-/- mice. The gene profiles of each population will be compared between the two strains of mice. Moreover, the efferocytosis ability and the impact of efferocytosis on the cell phenotype will be compared in each hepatic MΦ population from WT and gp91phox-/- mice.