Aryl hydrocarbon receptor and bilirubin as therapeutic target for ICH

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After intracerebral hemorrhage (ICH), phago(endo)cytosis of hematoma components [erythrocytes (RBC), hemoglobin (Hb) and heme], by microglia/macrophages (MMΦ) is essential for removal/detoxification of the hematoma, resolution of inflammation, and restoration of brain homeostasis for optimal neurological recovery. Thus, strategies for protecting MMΦ from injury during engulfment of toxic hematoma components is critical for the efficiency of MMΦ in clearing the hematoma after ICH. Upon engulfment of RBC/Hb/heme from the hematoma, MMΦ express heme oxygenase 1 (HO1; encoded by Hmox1), which catabolizes heme to produce large amounts of bilirubin (BrB) within MMΦ. Normally BrB is a beneficial and potent antioxidant; however, when intracellular BrB accumulates to very high concentrations, it may reversibly inhibit HO1 activity, thus reducing MMΦ' function and even precipitate onto biological membranes or nucleic acids (due to its poor water solubility), causing injury and compromising MMΦ' integrity. On the cellular level, BrB acts as an endogenous agonist for a pleotropic transcription factor, aryl hydrocarbon receptor (AhR), a protein that, based on prior research and our preliminary data, plays essential roles in supporting MMΦ for their integrity and function during hematoma clearance to enhance brain recovery after ICH. Our preliminary studies established that intracellularly elevated free BrB in microglia (MΦ), during erythrophagocytosis, activates AhR to promote transcription of BrB handling proteins, ligandins [(LGN/glutathione S-transferases), which bind fBrB to increase its cytosol solubility] and multidrug resistance protein 1 [(Mrp1)14, 15, which mediates efflux of BrB from the intracellular compartment to the extracellular space]. Without fast clearance of intracellularly accumulating fBrB, MΦ are injured and function less efficiently, and produce large amount of proinflammatory factors that could cause severe brain damage. In addition, we established that BrB-activated AhR promotes phagocytosis and upregulates the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), a master regulator of cellular oxidative defense for hematoma detoxification, and a potential therapeutic target for ICH. Furthermore, we established that AhR activity regulates RelB nuclear translocation, suggesting that AhR may also interact with RelB to transactivate genes involving inflammation resolution. Ultimately, using the mouse model of ICH, we found very promising therapeutic benefits of AhR agonist ITE19-21, alone and even more so in combination with the activator of Nrf2 (sulforaphane, SF), regarding neurological outcome and hematoma clearance. Our hypothesis is that after ICH, activation of AhR/RelB in MMΦ during hematoma removal by BrB (or other non-toxic AhR activators) is vital for preserving MMΦ' survival/phagocytic functions, avoiding self-inflicted damage, retention of reparative phenotype, ultimately leading to a more efficient MMΦ-mediated hematoma clearance and repair after ICH. Activation of AhR could be a novel therapeutic target for ICH.