The long-term goal of our research is to elucidate the mechanisms by which environmental chemicals induce chronic inflammation that leads to autoimmune diseases, to develop biomarker(s) for early detection of exposure-related symptoms, to identify targets, and to devise strategies for therapeutic intervention of environment-linked autoimmune hepatitis (AIH). Using autoimmune-prone MRL+/+ mice, we have shown that trichloroethene (TCE), an environmental contaminant and widely used industrial chemical, causes chronic inflammation and AIH. The central hypothesis of this application is that chronic exposure to TCE causes an imbalance between increased apoptosis and reduced clearance of apoptotic bodies due to compromised Kupffer cells, leading to T cell-mediated chronic inflammation of the liver (AIH), and that aberrant regulation of miRNAs contributes to this process. We will test this hypothesis by pursuing three Specific Aims.
Aim 1 : Our preliminary data from MRL+/+ mice exposed to TCE indicate that progression to liver inflammation, autoimmunity, and AIH is preceded by increased apoptosis and accumulation of apoptotic bodies. Based upon these novel observations, we propose that the delayed clearance of apoptotic bodies contributes to secondary necrosis, leading to inflammation, autoimmunity and ultimately AIH. This will be studied thoroughly by evaluating TCE-mediated apoptosis, clearance of apoptotic bodies, functional competency of Kupffer cells, and characterization of AIH in its progressive development.
Aim 2 : We have shown that chronic exposure to TCE results in lymphocyte infiltration into the liver. We will now establish the contribution of T and B cells to AIH in TCE-exposed MRL+/+ mouse livers by using a series of depletion and adoptive transfer experiments and functional characterization of lymphocyte subpopulations. To elucidate the key mechanisms of T helper cell activation and autoantibody production, we will investigate functions of hepatic dendritic cells in antigen presentation in the liver following TCE exposure.
Aim 3 : We have demonstrated a differential expression of mouse liver miRNAs following TCE exposure. To establish their role in TCE-mediated AIH, we will (a) evaluate the expression of relevant miRNAs in hepatocytes, Kupffer cells, and lymphocytes isolated from the liver, and (b) induce/inhibit relevant miRNA(s) in these cells from control and TCE-treated MRL+/+ mice, and correlate the miRNA profile with changes in their downstream targets associated with apoptosis, inflammation and autoimmunity. Furthermore, plasma samples from mice will also be screened for relevant miRNAs, since a differential miRNA profile in the plasma has the potential to serve as a biomarker of AIH. This project will be performed by our existing strong interdisciplinary team and will provide in-depth mechanistic information on how environmental chemicals contribute to chronic inflammatory diseases such as AIH.
Health Relevance: Environmental and/or occupational exposure to trichloroethene (TCE) has been linked to autoimmune diseases, such as autoimmune hepatitis. However, there is little experimental evidence showing a cause-and-effect relationship among TCE exposure, autoimmunity, and autoimmune hepatitis. The proposed research will elucidate the mechanism by which TCE causes inflammatory autoimmune hepatitis, develop biomarker(s) for early detection, and identify targets to devise preventive strategies and therapeutic interventions.
