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 TNF? 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 NF?B- mediated cytokine production, contributing to Th17 induction, defective Th1 response and increasing severity of infection with enteric bacteria.
Abusive alcohol consumption is a major public threat and an important cause of mortality and morbidity that affects hundreds of millions of individuals worldwide. We propose to study the effect of alcohol on a special compartment of the immune system: plasmacytoid dendritic cells (pDCs). pDCs control the body's defense against infections and other forms of tissue injury. New insights expected to emerge from these novel studies could significantly increase our knowledge of how ethanol impairs response to tissue injury and induces liver damage, thus providing the field with new therapeutic targets.
| Voigt, Robin M; Forsyth, Christopher B; Shaikh, Maliha et al. (2018) Diurnal variations in intestinal barrier integrity and liver pathology in mice: implications for alcohol binge. Am J Physiol Gastrointest Liver Physiol 314:G131-G141 |
| Magdaleno, Fernando; Ge, Xiaodong; Fey, Holger et al. (2018) Osteopontin deletion drives hematopoietic stem cell mobilization to the liver and increases hepatic iron contributing to alcoholic liver disease. Hepatol Commun 2:84-98 |
