Heat shock protein 90 in alcoholic liver disease: targeting macrophage Function

酒精性肝病中的热休克蛋白 90：靶向巨噬细胞功能

• 批准号: 10704118
• 负责人: Pranoti Mandrekar
• 金额: $ 56.18万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10704118
• 关键词: Acetylation; Affect; Alcohol abuse; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Bioenergetics; Cell Nucleus; Cellular Stress; Chromatin; Chronic; Cirrhosis; Cytoplasm; Data; Disease model; Economic Burden; Endoplasmic Reticulum; Endothelial Cells; Enzymes; Epigenetic Process; Ethanol; Fatty Liver; Funding; Future; GRP78 gene; Gene Expression; Genes; Glucose Transporter; Glycolysis; HIF1A gene; HSF1; HSP 90 inhibition; Health; Heat-Shock Proteins 90; Hepatocyte; Hexokinase 2; Human; In Vitro; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1 beta; Investigation; Kupffer Cells; Liver; Liver diseases; Macrophage; Macrophage Activation; Malignant Neoplasms; Mediating; Mediator; Messenger RNA; Metabolic; Metabolic Pathway; Metabolism; Molecular Chaperones; Mus; Myelogenous; Pathogenicity; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Primary carcinoma of the liver cells; Protein Isoforms; Proteins; Proteome; Reporting; Resolution; Role; SLC2A1 gene; Signal Transduction; Signaling Molecule; Steatohepatitis; Stress; TLR4 gene; TREM2 gene; activating transcription factor 3; aerobic glycolysis; clinical development; endoplasmic reticulum stress; extracellular vesicles; immune activation; in vivo; inhibitor; lipid metabolism; liver inflammation; liver injury; monocyte; nanoparticle; novel; novel therapeutics; paralogous gene; prevent; proteostasis; receptor; therapeutic target; tissue injury

ABSTRACT Liver immune cell activation is central to alcohol associated liver disease (ALD) and is poorly understood. The protein homeostasis network/pathways are crucial in safeguarding the cellular proteome from cellular stress. Amongst these, proteostasis mediator HSP90 is widely studied and extensively explored as a therapeutic target in cancer. We reported two isoforms of HSP90, HSP90AA1 (stress inducible cytoplasmic HSP90) and HSP90B1/GP96 (Endoplasmic reticulum paralog of HSP90) are important in ALD. These studies point to a pathophysiological role for HSP90 in ALD. Studies during the last funding period of this project established that liver targeting of HSP90 inhibitor 17-DMAG using nanoparticles in ALD can prevent and reverse liver injury, GP96/HSP90B1 deficiency in macrophages facilitates resolution of liver inflammation and ALD, M-TLR4 deficient mice are not protected from ALD, inhibition of HSP90 reduced NLRP3 inflammasome activity decreasing IL-1β protein and HSF1 partially contributes to reduced pro-inflammatory signaling, whereas deficiency of HSF1 did not protect from ALD, suggesting that HSF1 does not contribute to resolution of ALD. In the next project period we will investigate mechanisms mediated by HSP90AA1 and HSP90B1/GP96 in alcohol induced liver macrophage activation resulting in ALD. We propose that HSP90 induces inflammation by alternate mechanisms (independent of HSP90/TLR4 axis), for instance macrophage aerobic glycolysis via epigenetic mechanisms or HIF1α. In our preliminary data, we found that HSP90AA1 is detected in the nucleus in ALD and its inhibition can modulate expression of chromatin-modifying enzymes. Pilot data also reveal that inhibition of HSP90AA1 reduces alcohol mediated induction of glucose transporter (SLC2a1/GLUT1) and hexokinase II, two important mediators of glycolysis, suggesting a role for HSP90 in metabolic programming of M1 macrophages in ALD. On the other hand, HSP90B1/GP96 induced preferably in liver macrophages promotes inflammation via glycolysis and its inhibition induces GRP78+ATF3+Trem2+ restorative/reparative macrophages resolving ALD. We hypothesize that alcohol induced HSP90AA1 facilitates macrophage aerobic glycolysis via epigenetic mechanisms whereas HSP90B1/GP96 and ER stress facilitate macrophage glycolysis via HIF1α in ALD. Inhibition of HSP90 in ALD induces ATF3+Trem2+ reparative macrophages using OXPHOS facilitating protection. The specific Aims of this proposal are - 1) To identify HSP90AA1 mediated epigenetic and metabolic programming of macrophages in murine ALD in vivo and human AH PBMCs in vitro. 2) To characterize the significance of macrophage-specific HSP90B1/GP96 in macrophage metabolism and assess significance of ATF3 and TREM2 in macrophages conferring protection from liver injury. Collectively, during the next project period our studies will identify novel metabolic and epigenetic mechanisms regulated by HSP90 and characterize reparative macrophages crucial in resolution of ALD. Studying these pathways in mouse ALD model and human AH patient monocytes will provide basis for future clinical development of HSP90 in ALD.

抽象的 肝脏免疫细胞激活对酒精相关的肝病（ALD）至关重要，并且知之甚少。 蛋白质稳态网络/途径对于保护细胞蛋白质组免受细胞应激至关重要。 其中，广泛研究了蛋白质的介体HSP90并广泛探讨了治疗靶标 在癌症中。我们报道了HSP90，HSP90AA1（应力诱导细胞质HSP90）和两种同工型 Hsp90b1/gp96（HSP90的内质网旁系同源物）在ALD中很重要。这些研究指出 HSP90在ALD中的病理生理作用。在该项目的最后一个资金期间的研究确定 使用ALD中的纳米颗粒对Hsp90抑制剂17-DMAG的肝靶向可以预防和逆转肝损伤， GP96/HSP90B1巨噬细胞设施中的缺乏症，肝脏注射和ALD，M-TLR4缺乏症 小鼠不受ALD的保护，抑制Hsp90降低NLRP3炎性体活性，降低了IL-1β 蛋白质和HSF1部分有助于减少促炎信号传导，而HSF1的缺乏DID 不受ALD的保护，表明HSF1不会促进ALD的解决。在下一个项目期间 我们将研究由HSP90AA1和HSP90B1/gp96介导的酒精诱导肝脏介导的机制 巨噬细胞激活导致ALD。我们建议HSP90通过替代机制诱导注射 （独立于HSP90/TLR4轴），例如通过表观遗传机制或 HIF1α。在我们的初步数据中，我们发现在ALD的核中检测到HSP90AA1，其抑制作用可以 调节染色质修饰酶的表达。试验数据还表明，抑制HSP90AA1 减少酒精介导的葡萄糖转运蛋白（SLC2A1/GLUT1）和己糖激酶II的诱导，两个重要 糖酵解的介质，表明HSP90在ALD中M1巨噬细胞代谢编程中起作用。在 另一方面，HSP90B1/GP96在肝巨噬细胞中优先诱导了通过糖酵解促进注射 及其抑制作用诱导GRP78+ATF3+TREM2+恢复/修复巨噬细胞解决ALD。我们 假设酒精诱导HSP90AA1的最爱巨噬细胞有氧糖酵解通过表观遗传学 机理，而HSP90B1/GP96和ER应力通过ALD中的HIF1α促进巨噬细胞糖酵解。 ALD中HSP90的抑制会诱导ATF3+ Trem2+使用Oxphos促进的巨噬细胞 保护。该提案的具体目的是-1）识别HSP90AA1介导的表观遗传和代谢 体内鼠类ALD和人类AH PBMC的巨噬细胞的编程。 2）表征 巨噬细胞特异性HSP90B1/GP96在巨噬细胞代谢中的重要性和评估的显着性 巨噬细胞中的ATF3和TREM2会议保护免受肝损伤。在下一个项目中共同 我们的研究将确定由HSP90调节的新型代谢和表观遗传机制，并表征 修复性巨噬细胞对ALD解决至关重要。在小鼠ALD模型和人类中研究这些途径 AH患者的单核细胞将为ALD中HSP90的未来临床开发提供基础。

项目成果

A recent perspective on alcohol, immunity, and host defense.

• DOI: 10.1111/j.1530-0277.2008.00842.x
• 发表时间: 2009-02
• 期刊: Alcoholism, clinical and experimental research
• 作者: Szabo G;Mandrekar P
• 通讯作者: Mandrekar P

Sexual Dimorphism in Alcohol Induced Adipose Inflammation Relates to Liver Injury.

• DOI: 10.1371/journal.pone.0164225
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Fulham MA;Mandrekar P
• 通讯作者: Mandrekar P

Focus on: Alcohol and the liver.

重点关注：酒精和肝脏。

• 发表时间: 2010
• 期刊: Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism
• 作者: Szabo,Gyongyi;Mandrekar,Pranoti
• 通讯作者: Mandrekar,Pranoti

VSL#3 probiotic treatment attenuates fibrosis without changes in steatohepatitis in a diet-induced nonalcoholic steatohepatitis model in mice.

• DOI: 10.1002/hep.22711
• 发表时间: 2009-03
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Velayudham, Arumugam;Dolganiuc, Angela;Ellis, Michael;Petrasek, Jan;Kodys, Karen;Mandrekar, Pranoti;Szabo, Gyongyi
• 通讯作者: Szabo, Gyongyi

Signalling pathways in alcohol-induced liver inflammation.

• DOI: 10.1016/j.jhep.2009.03.007
• 发表时间: 2009-06
• 期刊: Journal of hepatology
• 影响因子: 25.7
• 作者: Mandrekar P;Szabo G
• 通讯作者: Szabo G