The impact of Aryl hydrocarbon receptor signaling on Toll like receptor-mediated inflammation

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Project Summary/Abstract The aryl hydrocarbon receptor (AhR) plays an important role in regulating immune responses and exposure to AhR-activating compounds, including environmental toxicants such as dioxins may contribute to the dysregulation of cytokines and the development of immune system disorders. The ligand-dependent activation of AhR can promote differentiation of inflammatory T helper Th17 cells or lead to profound immunosuppression and an increase of regulatory T cells. Significant gaps exist in our understanding of how the AhR regulates the inter- and intracellular communication processes between dendritic cells (DC) and other immune cells on the molecular level, which is of central importance to understanding both physiologic and pathophysiologic immune reactions mediated through AhR. The overall goal of this proposal is to identify the functional role of the AhR and its specific repressor (AhRR) interacting with Toll-like receptor (TLR) and NFkB signaling in controlling function and differentiation of DC and T-cell activation. The reported dysregulation of TLR and NFkB signaling by AhR ligands may be key steps in triggering immune system disorders. The transcriptional repressor of the AhR, the AhRR is implemented in the AhR pathway, although much remains to be elucidated at the level of TLR and NFkB signaling. In transgenic mice overexpressing AhRR we discovered that AhRR is critically involved in regulation of dioxin-induced inflammatory gene expression as well as LPS-mediated inflammatory responses and LPS shock. Thus, the AhRR Tg mice give us the opportunity to recognize how AhRR is involved in the regulation of TLR-mediated responses and other parts of the immune system. Bone-marrow derived DC from genetic mouse models as well as human DC, will be used to investigate how DC are regulated through ligand- induced activation of the AhR and inflammatory signals via TLR/NFkB. A genome-wide identification of AhR/Rel binding sites will be conducted and related to gene expression analysis. Mutants of binding sites will be generated to validate whether a particular binding event is actually required to regulate the expression of target genes. Protein-protein interaction studies will identify the specific interacting domains of AhR and Rel proteins and provide insight into how these interactions impact the functional activity of each protein and the outcome of AhR/NFkB crosstalk. A novel in vivo method to monitor immune responses noninvasively via Positron Emission Tomography (immuno-PET) imaging will be used to ultimately show how AhR ligands modify TLR-mediated recruitment and accumulation of DC, neutrophils, B cells, and T cells in vivo. This study can provide a definite link and mechanism between the exposure to AhR activating compounds and the development of inflammatory chronic diseases. Findings will allow for more clearly defined endpoints to assess the effects and toxicity of AhR activating ligands including environmental pollutants. This study will also provide new concepts for future innovative uses of AhR and AhRR as molecular targets for therapeutic applications in inflammation, infection, and chronic diseases.