Aryl hydrocarbon receptor and bilirubin as therapeutic target for ICH

The project focuses on understanding how microglia/macrophages (MMΦ) clear hematoma components (erythrocytes, hemoglobin, heme) after intracerebral hemorrhage (ICH). It explores the role of heme oxygenase 1 (HO1) in producing bilirubin (BrB) within MMΦ, and how high intracellular BrB concentrations can inhibit HO1 and injure MMΦ. The research hypothesizes that BrB acts as an endogenous agonist for the aryl hydrocarbon receptor (AhR), which is crucial for MMΦ integrity and function during hematoma clearance. Preliminary studies show that BrB-activated AhR promotes transcription of BrB handling proteins (ligandins, Mrp1), enhances phagocytosis, upregulates nuclear factor erythroid 2-related factor 2 (Nrf2), and regulates RelB nuclear translocation. The ultimate goal is to demonstrate that activating AhR/RelB in MMΦ, either by BrB or other non-toxic activators, preserves MMΦ survival and phagocytic functions, leading to more efficient hematoma clearance and repair after ICH. Mouse model studies have shown therapeutic benefits of the AhR agonist ITE, particularly in combination with the Nrf2 activator sulforaphane (SF).