GPR81 & GPR109a Regulate Innate Immune Injury in Sterile Inflammation

探地雷达81

• 批准号: 8683551
• 负责人: Rafaz Hoque
• 金额: $ 8.33万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-03 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8683551
• 关键词: ARRB2; Acetaminophen; Acute; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Biological Assay; Caerulein; Cell Surface Receptors; Cell surface; Cells; Cytoprotective Agent; Data; Functional disorder; G-Protein-Coupled Receptors; Galactosamine; Glycolysis; Hepatitis; Immune; Immune response; Immune system; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Knockout Mice; Kupffer Cells; Ligands; Liver; Mediating; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mus; Nicotinic Acids; Organ; Organ failure; Pancreas; Pancreatic Injury; Pancreatitis; Pathway interactions; Pattern; Peritoneal; Peritoneal Macrophages; Phenotype; Process; Proteins; Regulation; Resolution; Rodent Model; Role; Signal Transduction; Site; Sterility; Supplementation; TLR4 gene; Tissues; Work; acute liver injury; acute pancreatitis; beta-Hydroxybutyrate; cell injury; heme oxygenase-1; immune activation; in vivo; in vivo Model; liver injury; macrophage; mortality; public health relevance; receptor; response; toll-like receptor 4; transcription factor

Acute injury of the liver or pancreas results in a rapid sterile inflammatory response (SIR) through TOLL- like receptor (TLR) stimulation characterized by edema, cellular infiltrate, and further parenchymal cell death. Many lines of evidence point towards the SIR having a vital role in pancreatic and liver damage. The signals which promote resolution of the SIR are poorly understood. Lactate and beta- hydroxybutyrate are produced at sites of inflammation and signal through specific cell curface receptors GPR81 and GPR109a, respectively. Our preliminary data demonstrate that in acetaminophen or LPS/galactosamine induced acute liver injury and in caerulein-induced acute pancreatitis: i. supplementation with lactate or beta-hydroxybutyrate decreases inflammation and tissue injury in the liver and pancreas and decreases TLR driven pro- inflammatory responses in macrophages in vitro, ii. in vivo knockdown of GPR81 or GPR109a markedly enhances liver injury, reduces induction of the cytoprotectant hmox1, and promotes mortality in LPS/galactosamine induced hepatitis, iii. GPR81 and GPR109a expression is predominantly in the macrophage compartment in the liver, and iv. lactate and beta-hydroxybutyrate require the GPR interacting protein ARRB2 for suppression of TLR4 driven pro-inflammatory responses in macrophages. It is known that ARRB2 signaling suppresses NF-¿B dependent pro-inflammatory signaling downstream of TLR receptors. It is also known that the GPR109a agonist niacin induces hmox1 through an NFE2 transcription factor dependent pathway. HMOX1 is known to promote polarization of macrophage immune phenotype towards the M2 alternatively active state and away from the M1 classical pro- inflammatory state. We hypothesize that GPR81 and GPR109a receptors and their ligands limit innate immune mediated inflammation through beta-arrestin 2 (ARRB2) pathways and NFE2-dependent heme-oxygenase 1 (HMOX1) pathways. AIM 1: Identify the contribution of ARRB2 and NFE2 signaling to GPR81 and GPR109a mediated modulation of the sterile inflammatory response through use of knockout mice for arrb2 and nfe2 and study of isolated macrophages and in vivo models of acute pancreatitis and acute liver injury. AIM 2: Determine synergy between GPR81 and GPR109a signaling in inducing hmox1 and suppressing NF-¿B dependent pro-inflammatory responses to TLR4 and TLR9 ligands in isolated macrophages, in vivo with LPS treatment, and in vivo in LPS/cearulein pancreatitis. The proposed work will identify a detailed cellular and molecular mechanism for GPR81 and GPR109a mediated regulation of the sterile inflammatory response.

急性肝或胰腺损伤通过Toll-Toll导致快速无菌炎症反应(SIR)。 类受体(TLR)刺激的特征是水肿、细胞浸润和进一步的实质细胞 死亡。许多证据表明，SIR在胰腺和肝脏损伤中起着至关重要的作用。 对促进SIR分辨率的信号知之甚少。乳酸盐和β- 羟丁酸是在炎症部位产生的，并通过特定的细胞表面受体传递信号 GPR81和Gpr109a。 我们的初步数据表明，在扑热息痛或内毒素/氨基半乳糖诱导的急性肝损伤中 在雨蛙素诱导的急性胰腺炎中：I.补充乳酸或β-羟基丁酸酯 减少肝脏和胰腺的炎症和组织损伤，降低TLR驱动的促进性 巨噬细胞体外炎症反应，II。GPR81或GPR109a在体内的显著下调 增强肝脏损伤，减少细胞保护剂Hmox1的诱导，并提高死亡率 脂多糖/氨基半乳糖诱导的肝炎，III。GPR81和Gpr109a的表达主要集中在 肝内巨噬细胞室，静脉注射。乳酸盐和β-羟基丁酸盐需要探地雷达 相互作用蛋白ARRB2抑制TLR4诱导的巨噬细胞促炎反应。 已知ARRB2信号在下游抑制依赖于核因子-B的促炎信号 TLR受体。Gpr109a激动剂烟酸通过NFE2诱导Hmox1也是已知的 转录因子依赖途径。已知Hmox1促进巨噬细胞极化 免疫表型向M2交替活跃状态转变，远离经典的M1前状态。 炎症状态。 我们推测GPR81和GPR109a受体及其配体限制了天然免疫介导的免疫 β-arrestin 2(ARRB2)途径和NFE2依赖的血红素加氧酶1引起的炎症 (Hmox1)路径。 目的1：确定ARRB2和NFE2信号在GPR81和Gpr109a介导中的作用 通过使用arrb2和nfe2基因敲除小鼠来调节无菌炎症反应 急性胰腺炎和急性肝损伤的巨噬细胞分离和体内模型的研究。 目的2：确定GPR81和Gpr109a信号在诱导Hmox1和抑制Hmox1中的协同作用 巨噬细胞对TLR4和TLR9配体的促炎症反应 体内注射脂多糖治疗，体内注射脂多糖/青蒿素胰腺炎。 拟议的工作将确定GPR81和Gpr109a的详细细胞和分子机制 无菌炎症反应的中介调节。