Alcohol Consumption Accumulation of Monocyte Derived Macrophages in Female Mice Liver Is Interferon Alpha Receptor Dependent.

Monocytes develop in the bone marrow from the hematopoietic stem cells and represent heterogeneous phagocyte cells in the circulation. In homeostatic and inflammatory conditions, after recruitment into tissues, monocytes differentiate into macrophages and dendritic cells. Alcohol use causes about 3.3 million worldwide deaths per year, which is about 5.9% of all deaths. In the United States and Europe, alcohol use disorders represent the fifth leading cause of death. Females are more susceptible to alcoholic liver injury in both humans and mice. Strikingly, we still do not know how much of this difference in tissue injury is due to the differential effect of alcohol and its toxic metabolites on a) parenchymal or resident cells and/or b) immune response to alcohol. Therefore, we used a model of chronic alcohol exposure in mice to investigate the dynamics of monocytes, an innate immune cell type showed to be critical in alcoholic liver injury, by using immunophenotypic characterization. Our data reveal a sex-dimorphism of alcohol response of hepatic monocytes in female mice that is interferon receptor alpha dependent. This dimorphism could shed light on potential cellular mechanism(s) to explain the susceptibility of females to alcoholic immunopathogenesis and suggests an additional targetable pathway for alcoholic liver injury in females.

Sex specific effect of alcohol on hepatic plasmacytoid dendritic cells.

Alcoholic liver disease includes a spectrum of clinical and histological entities. They result from the combined direct effect of alcohol and its metabolites on immune cells and resident tissue cells. In humans and mice, females are more susceptible to alcoholic liver injury than males. Despite being involved in sex specific differences of immune mediated tissue injury, plasmacytoid dendritic cells (pDCs) have not been thoroughly assessed as a cellular target of alcohol in humans or mice. Therefore, Meadows-Cook diet was used to study alcohol effect on hepatic dendritic cells. Alcohol consumption for 12 weeks increased hepatic pDCs in female mice. The expression of the C-C chemokine receptor type 2 (CCR2) increased in hepatic pDC of alcohol-fed female mice. Bone marrow transplant chimera showed CCR2 dependent bone marrow egress of pDCs. Chronic alcohol exposure has a sex specific effect on hepatic pDCs population that may explain sex differences to alcoholic liver disease.