Targeting mononuclear phagocytes development in alcohol induced liver damage: pathological and immunological pathways

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ABSTRACT Alcohol consumption causes a spectrum of clinical illness and morphological changes that range from fatty liver to hepatic inflammation (alcoholic hepatitis) and progressive fibrosis (alcoholic cirrhosis). Alcoholic liver disease has an incompletely known pathogenesis and specific treatments are lacking. It is an extremely common disease with significant mortality and morbidity. T cellular immune responses were shown to be affected and involved in these outcomes. Decreased resistance to infections and an abnormal systemic inflammatory response to infections are common events associated with alcohol consumption. Alcohol exposure has complex effects on gut permeability and the immune system, resulting in activation of mononuclear phagocytes, steatosis, neutrophil recruitment and altered cellular immune responses. Dendritic cells (DC), professional antigen presenting cells, are emerging as an important regulator of tissue microenvironment. After four decades of research, we now know that DC arise from a hematopoietic lineage distinct from other leukocytes (including monocytes and macrophages), establishing the DC lineage as a unique hematopoietic branch. Several DC populations coexist in mice and humans with similar developmental pathways: (1) conventional DC (cDC) involved in antigen presentation; (2) plasmacytoid DC (pDC), characterized by a high capacity of cytokine production. pDC development and maintenance is under control of a transcription factor: E2-2. pDC release from marrow is dependent of CCR2. These data, combined with our central preliminary observation showing increased hepatic pDC in a well-established model of chronic alcohol consumption, sparked the idea of a potential effect of alcohol on pDC development with accumulation of hepatic pDC that reshapes the hepatic pro-inflammatory cytokine milieu and results in abnormal T helper 1 and Th17 cellular immune responses known to be present after chronic alcohol consumption. Our long-term goal is to investigate the effects of alcohol on DC homeostasis and their effect on immune and pathological characteristics seen in alcoholic liver disease. Our central hypothesis is that alcohol induces abnormal DC development and hepatic pDC accumulation. The high cytokine production capacity of pDC stimulated by bacterial products reaching the liver may contribute to hepatic and blood TNFα production, a well-known central mediator of alcoholic liver injury. Further, pDC participate in increased generation of Th17 (well-known to be directly involved in promoting neutrophilic inflammation) and down-regulation of Th1 immune responses. We will test our central hypothesis through the following interrelated Specific Aims: (1) We will test whether alcohol consumption increases pDC release from bone marrow by increasing E2-2 dependent pDC development and their CCR2 dependent egress. (2) We will test if alcohol primes hepatic pDC for NFκB- mediated cytokine production, contributing to Th17 induction, defective Th1 response and increasing severity of infection with enteric bacteria.