Other Affiliation(s):
Program In Immunology and Virology
Graduate School of Biomedical Sciences

MACROPHAGE ACTIVATION IN LIVER DISEASES

Research in my laboratory focuses on understanding the signaling mechanisms involved in macrophage activation during liver injury. The physiological function of the liver is elimination of pathogens and antigens from the blood for which mounting of an immune response is required. To avoid unnecessary activation of the immune system, the liver develops a local immune response followed by induction of peripheral tolerance towards the antigen. When stressful agents such as pathogens or environmental insults challenge the liver for extended periods of time and their elimination is not possible, inflammation and injury follows. The onset of inflammation in the liver is followed by fibrosis, cirrhosis and liver failure. Thus, studying the mechanisms involved in liver inflammation will provide major insights into pathogenesis of liver disease.  

Using various in vivo and in vitro models, we are studying the role of innate immune signaling pathways, their crosstalk with oxidative stress related mechanisms leading to pro-inflammatory cytokine production.  We are also focusing on investigating the role of chemokine responses and their effect on recruitment of bone-marrow derived cells and immune cells in the liver during development and progression of liver disease. Currently two main areas of focus are: 

1) Oxidative stress and Inflammation in alcoholic liver diseases

Characterization of an interplay of immune and oxidative stress related mechanisms involved in mediating the effects of acute and chronic alcohol consumption, and epigenetic pathways altered in chronic liver diseases using alcoholic and non-alcoholic liver disease models are being studied. We hypothesize that alcohol activates oxidative stress mediated molecular chaperones affecting key signaling molecules that play a pathogenic role in alcoholic liver injury. Our recent studies show that heat shock protein expression, particularly hsp90 and hsp70, are altered by acute and chronic alcohol exposure in innate immune cells resulting in regulation of inflammatory responses. Our studies are currently using molecularly targeted translational approaches to evaluate hsp90 and hsp70 as a therapeutic targets in macrophage activation and liver diseases such as alcoholic liver disease and fibrosis.

2) Chemokines and importance of immune liver cell types in liver injury

In this project, the dynamic role of immune cells and bone marrow derived hematopoietic cells and their cross talk with other liver cell types in promoting liver diseases is being investigated. Liver macrophages, dendritic cells, NK and NKT cells play an important function in development and progression of liver disease. We propose to unravel the role of chemokines in recruitment of immune cells in the liver and modulate chronic liver injury. Specifically, recent studies in our laboratory have identified a significant role for a CC-chemokine, monocyte chemoattractant protein -1 (MCP-1) in induction of fatty liver disease. Other chemokines and chemokine receptors are also being explored to determine the role of MCP-1 in mediating inflammatory processes leading to alcoholic liver injury.