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: 10408850
• 负责人: Jaroslaw Aronowski
• 金额: $ 47.13万
• 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/10408850
• 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; 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.

脑内出血（ICH）后，血肿成分的phago（内部）细胞增多[红细胞（RBC）， 通过小胶质细胞/巨噬细胞（MM或），血红蛋白（Hb）和血红素]对于去除/排毒至关重要 血肿，感染的分辨率和脑体内平衡的恢复，以获得最佳的神经系统恢复。 那就是保护MMφ免受毒性血肿成分造成伤害的策略至关重要 MMφ在ICH后清除血肿的效率。 在血肿中吞没RBC/Hb/Heme后，MMφ表达血红素氧酶1（HO1；由 HMOX1），它使血红素分解以在MMφ内产生大量胆红素（BRB）。通常BRB是 有益和潜在的抗氧化剂；但是，当细胞内BRB积聚至非常高的浓度时， 可能可逆地抑制HO1活性，从而降低MMφ的功能，甚至沉淀到生物膜上 或核酸（由于其水溶性差），导致损伤并损害MMφ的完整性。 在细胞水平上，BRB充当全元转录因子，芳基烃的内源性激动剂 接收器（AHR），一种蛋白质，基于先前的研究和我们的初步数据，在 支持MMφ在血肿清除期间的完整性和功能，以增强ICH后的大脑恢复。 我们的初步研究确定，在小胶质细胞（Mφ）中细胞内升高的自由BRB在期间 红细胞吞噬作用，激活AHR以促进BRB处理蛋白的转录，配体蛋白 [（LGN/谷胱甘肽S-转移酶），结合FBRB以增加其细胞质溶液]和多药电阻 蛋白1 [（MRP1）14，15，它介导了从细胞内室到细胞外空间的BRB外排]。 如果没有快速清除细胞内积累的FBRB，Mφ受伤，功能效率较低，并且功能较低，并且 产生大量促炎性因素，可能导致严重的脑损伤。另外，我们 确定BRB激活的AHR促进吞噬作用并更新核因子的表达 红细胞2相关因子2（NRF2），一种用于血肿解毒的细胞氧化物防御的主要调节剂， 以及ICH的潜在治疗靶点。此外，我们确定AHR活性调节了Relb核 易位，表明AHR也可能与RELB相互作用，以涉及注射的反式激活基因 解决。最终，使用ICH的鼠标模型，我们发现了AHR的非常有希望的治疗益处 激动剂ITE19-21，单独，甚至与NRF2（Sulforaphane，SF）相结合的激动剂 神经系统结果和血肿清除率。 我们的假设是，在ICH之后，通过BRB的血肿去除血肿（或其他 无毒AHR激活剂）对于保留MMφ的生存/吞噬功能至关重要，避免自我损害 损坏，保留re谐表型，最终导致更有效的MMφ介导的血肿 ICH后清除和维修。 AHR的激活可能是ICH的新型治疗靶点。