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)后血肿成分吞噬(Endo)细胞增多[红细胞(RBC)， 小胶质细胞/巨噬细胞(MMΦ)的血红蛋白(Hb)和血红素]，是清除/解毒所必需的 血肿、炎症消退和脑内稳态的恢复，以实现最佳的神经恢复。 因此，保护MMΦ在吞噬有毒血肿成分期间免受伤害的策略对于 MM-Φ清除脑出血后血肿的疗效观察 当从血肿中吞噬红细胞/Hb/血红素时，MMΦ表达血红素加氧酶1(HO1；编码为 Hmox1)，在MMΦ中分解血红素以产生大量的胆红素(BRb)。通常，BRB是一种 有益且有效的抗氧化剂；然而，当细胞内BRB积累到非常高的浓度时，它 可能会可逆地抑制HO1的活性，从而降低MMΦ的功能，甚至沉淀到生物膜上 或核酸(由于其较差的水溶性)，造成伤害并损害MMΦ的完整性。 在细胞水平上，BRB作为一种多嗜性转录因子芳烃的内源性激动剂 受体(AhR)是一种蛋白质，根据先前的研究和我们的初步数据，它在 支持MMΦ在血肿清除过程中的完整性和功能，以促进脑出血后的脑恢复。 我们的初步研究证实，细胞内小胶质细胞(MΦ)的游离BRB在 红细胞吞噬作用，激活AhR促进BRB处理蛋白、配体的转录 [(LGN/谷胱甘肽S转移酶，结合fBrB以增加其胞浆溶解性]与多药耐药 蛋白1[(Mrp1)14，15，它介导BRB从细胞内室流出到细胞外空间]。 如果没有快速清除细胞内积累的fBrB，MΦ就会受到损伤，功能降低。 产生大量的促炎因子，可能导致严重的脑损伤。此外，我们 证实BRB激活的AhR促进吞噬功能并上调核因子的表达 红系相关因子2(NRF2)是血肿解毒的细胞氧化防御的主要调节因子。 是治疗脑出血的潜在靶点。此外，我们建立了AhR活性调节RelB核 易位，提示AhR也可能与RelB相互作用，反式激活涉及炎症的基因 决议。最终，在脑出血的小鼠模型上，我们发现了AhR非常有希望的治疗益处 激动剂ITE19-21单独使用，与NRF2激活剂(萝卜硫醚，SF)结合使用时更是如此。 神经转归和血肿清除。 我们的假设是，脑出血后，在血肿清除过程中MMΦ中AhR/RelB的激活 无毒的AHR激活剂)对于保护MMΦ的生存/吞噬功能至关重要，避免自伤 损伤、修复表型保留，最终导致更有效的MMΦ介导的血肿 脑出血后的清除和修复。AhR的激活可能成为治疗脑出血的新靶点。