Aryl hydrocarbon receptor and bilirubin as therapeutic target for ICH

芳烃受体和胆红素作为脑出血的治疗靶点

• 批准号: 10299427
• 负责人: Jaroslaw Aronowski
• 金额: $ 46.49万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299427
• 关键词: ABCB1 gene; Affect; Age; Agonist; Animals; Anti-Inflammatory Agents; Antioxidants; Aryl Hydrocarbon Receptor; Bilirubin; Binding; Biological; Blood; Brain; Brain Injuries; Cerebral hemisphere hemorrhage; Clinical; Cytoprotection; Cytosol; DNA; Data; Drug Metabolic Detoxication; Erythrocytes; Erythrophagocytosis; Excision; Excretory function; Extracellular Space; Functional disorder; Genes; Genetic Transcription; Glutathione S-Transferase; Health; Hematoma; Heme; Hemoglobin; Hemorrhage; Homeostasis; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Knockout Mice; Mediating; Membrane; Microglia; Molecular; Neurologic; Neurological outcome; Nuclear Translocation; Nucleic Acids; Pathway interactions; Phagocytes; Phagocytosis; Phenotype; Pigments; Play; Precipitation; Process; Production; Proteins; Pump; Receptor Activation; Recovery; Research; Resolution; Role; Small Interfering RNA; Solubility; Sulforaphane; Therapeutic; activating transcription factor; base; brain cell; brain repair; cell injury; heme oxygenase-1; in vivo; inhibitor/antagonist; injured; macrophage; mouse model; neurological recovery; new therapeutic target; nuclear factor-erythroid 2; preservation; prevent; repaired; response; restoration; sex; therapeutic target; transcription factor; water solubility

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.

脑出血（ICH）后，血肿成分[红细胞（RBC）]的吞噬（内腔）细胞增多，