The importance of innate immune cells in the pathophysiology of alcoholic liver injury is evident from animal models and human studies. Resident macrophages in the liver are activated by endotoxin in portal circulation to produce inflammatory cytokines. In addition to the pro-inflammatory cytokines, macrophages also produce chemokines that can contribute to alcoholic liver injury. Our preliminary studies show increased production of serum and liver tissue MCP-1 production after chronic alcohol feeding in mice. We also show that MCP-1 deficient mice exhibit significantly decreased liver injury after chronic alcohol feeding. Increased MCP-1 in the liver can promote monocyte/macrophage infiltration in the liver and contribute to inflammatory responses. Activation of monocyte/macrophages is pivotal to the development of alcoholic liver injury. We hypothesize that chronic alcohol exposure induces MCP-1 in the liver and its receptor, CCR2 on circulating monocyte/macrophages facilitating their recruitment to the liver. Altered MCP-1/CCR2 signaling could thus contribute to innate immune cell-mediated alcoholic liver injury. The objectives of the current application are to determine the role of MCP-1/CCR2 axis in alcohol-induced liver injury. Specifically, our focus will be to first perform a longitudinal analysis of MCP-1 expression in the liver and correlate these changes with alterations in resident and infiltrating macrophages in the liver after chronic alcohol feeding. Next, we will analyze the MCP-1 receptor, CCR2 on circulating monocytes after chronic alcohol feeding. We will also determine the effect of chronic alcohol on chemotaxis of CCR2-expressing monocyte/macrophages in an in vitro assay. Finally, using CCR2 knock out mice we will determine the pathophysiological significance of the MCP-1/CCR2 axis in alcohol- induced fatty liver injury. To achieve these objectives, the following specific aims are proposed: 1) Determine whether MCP-1 is required for alcohol-induced liver injury and intracellular mechanisms involved and 2) Investigate the effect of chronic alcohol on CCR2, a MCP-1 receptor, on circulating monocyte/macrophages its functional significance in alcohol-induced liver injury. Public Health Relevance: Alcoholic liver disease is a major health concern in the United States. The objectives of this application are to investigate the effect of CC-chemokine, monocyte chemoattractant protein-1 (MCP-1) and its receptor CC-chemokine receptor 2 (CCR2) on monocyte/macrophages into the liver and its contribution to the development of alcoholic liver injury. These mechanistic studies will identify the role of monocytes and macrophages and aid in developing therapies targeted to inhibit macrophage function during chronic alcohol consumption.

Public Health Relevance

Alcoholic liver disease is a major health concern in the United States. The objectives of this proposal are to investigate the effect of CC-chemokine, monocyte chemoattractant protein-1 (MCP-1) and its receptor CC-chemokine receptor 2 (CCR2) on monocyte/macrophages into the liver and its contribution to the development of alcoholic liver injury. These mechanistic studies will identify the role of monocytes and macrophages and aid in developing therapies targeted to inhibit macrophage function during chronic alcohol consumption.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AA017545-01A1
Application #
7661132
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Radaeva, Svetlana
Project Start
2010-09-10
Project End
2012-08-31
Budget Start
2010-09-10
Budget End
2012-08-31
Support Year
1
Fiscal Year
2010
Total Cost
$246,750
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Ambade, Aditya; Mandrekar, Pranoti (2012) Oxidative stress and inflammation: essential partners in alcoholic liver disease. Int J Hepatol 2012:853175
Nath, Bharath; Levin, Ivan; Csak, Timea et al. (2011) Hepatocyte-specific hypoxia-inducible factor-1ýý is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice. Hepatology 53:1526-37
Szabo, G; Mandrekar, P; Petrasek, J et al. (2011) The unfolding web of innate immune dysregulation in alcoholic liver injury. Alcohol Clin Exp Res 35:782-6
Mandrekar, Pranoti; Ambade, Aditya; Lim, Arlene et al. (2011) An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice. Hepatology 54:2185-97
Mandrekar, Pranoti (2011) Epigenetic regulation in alcoholic liver disease. World J Gastroenterol 17:2456-64
Szabo, Gyongyi; Mandrekar, Pranoti (2010) Focus on: Alcohol and the liver. Alcohol Res Health 33:87-96
Mandrekar, Pranoti; Szabo, Gyongyi (2009) Signalling pathways in alcohol-induced liver inflammation. J Hepatol 50:1258-66
Szabo, Gyongyi; Mandrekar, Pranoti (2009) A recent perspective on alcohol, immunity, and host defense. Alcohol Clin Exp Res 33:220-32