TNFR1 and regulation of inflammatory diseases

TNFR1 与炎症性疾病的调节

• 批准号: 10023078
• 负责人: Richard M Siegel
• 金额: $ 36.31万
• 依托单位: NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10023078
• 关键词: 5' -AMP-activated protein kinase; ARNTL gene; Anti-inflammatory; Autoimmune Diseases; Autoimmune Process; Biological Products; Cells; Chronic; Clinical; Cues; Disease; Dose; Endoplasmic Reticulum; Exhibits; Family; Fever; Functional disorder; Gene Expression; Generations; Genes; Genetic; Genomics; Germ-Line Mutation; Glucocorticoids; Glucose; Goals; Hepatocyte; Hypersensitivity; Hypoglycemia; Immune; Immune response; Inflammation; Inflammatory; Ketones; Knock-in Mouse; Lead; Light; Link; Lipopolysaccharides; Liver; Maintenance; Metabolism; Methotrexate; Mitochondria; Mitogen-Activated Protein Kinases; Modeling; Mus; Musculoskeletal Diseases; Mutant Strains Mice; Mutate; Mutation; NF-kappa B; National Human Genome Research Institute; Natural Immunity; Nutritional; Pathogenesis; Pathway interactions; Patients; Periodicity; Peripheral Blood Mononuclear Cell; Predisposition; Production; Proteins; Reactive Oxygen Species; Regulation; Resistance; Rheumatoid Arthritis; Role; Sepsis; Septic Shock; Serum; Signal Pathway; Signal Transduction; Somatic Mutation; Starvation; Syndrome; TNF gene; TNFRSF1A gene; Time; Time-restricted feeding; Tumor Necrosis Factor Receptor; Work; autoinflammatory; autosomal dominant mutation; circadian pacemaker; cytokine; feeding; immunoregulation; improved; insight; macrophage; mortality; mutant; novel strategies; symptom treatment; therapeutic target

Tumor Necrosis Factor (TNF) is central to the pathogenesis of many inflammatory diseases, acting primarily through the p55 Tumor Necrosis Factor Receptor 1 (TNFR1). Biologic agents have successfully targeted TNFR1 in rheumatoid arthritis and other inflammatory diseases. We are working with the Genetics and Genomics Branch in NHGRI to understand the pathophysiology of inflammation in patients with the TNF Receptor Associated Periodic Syndrome (TRAPS), a genetic autoinflammatory disease associated with dominant mutations in TNFR1. How TNFR1 mutations predispose to inflammation is not known. Blockade of TNF with biologic agents is only partially effective in treating the symptoms of TRAPS. We have found that TNFR1 mutant molecules associated with TRAPS are misfolded and accumulate in the endoplasmic reticulum. In more recent work, we have found that TNFR1 protein accumulates intracellularly in TRAPS patient peripheral blood mononuclear cells (PBMC) and knock-in mice harboring two independent TRAPS-associated TNFR1 mutations. Presence of the mutant TNFR1 protein specifically activates signaling in the MAP-Kinase pathway, while NF-kB activation was not affected. Cells from heterozygous TNFR1-mutant mice exhibited elevated production of pro-inflammatory cytokines and systemic hypersensitivity to lipopolysaccharide (LPS,) and TRAPS patient PBMC were hyper-responsive to low-dose LPS. In contrast, homozygous TNFR1-mutant mice were resistant to LPS-induced septic shock similarly to TNFR1 deficient mice. Hyperactivation of MAP kinases and enhanced inflammatory signaling are dependent on mitochondrial generation of reactive oxygen species, identifying mitochondrial ROS as a possible therapeutic target in TRAPS. These results shed new light on the pathogenesis of TRAPS and identify novel strategies for anti-inflammatory treatment in TRAPS and other inflammatory diseases. These studies spurred further studies on metabolism and inflammation. We investigated the potential role of AMP activated kinase (AMPK) as a target of methotrexate. We also investigated the effects of nutritional vs. light cues macrophage and hepatocyte gene expression and susceptibility to LPS induced sepsis. we found that susceptibility to lethal LPS challenge is regulated by the feeding, rather than light cycle, with the greater mortality at time of awakening reversed in mice subjected to time restricted feeding. Feeding-entrained susceptibility to sepsis was not accompanied by increased inflammatory cytokine production, and endogenous glucocorticoids, or starvation-related ketones did not correlate with mortality. Rather, hypoglycemia after LPS administration correlated with mortality, in line with recent results showing that maintenance of serum glucose is a key survival factor in early mortality in murine sepsis models and in clinical sepsis. We found that feeding-regulated susceptibility to sepsis was regulated in a liver-intrinsic manner by key circadian clock gene BMAL1, using mice in which this gene was conditionally deleted in the liver.

肿瘤坏死因子（TNF）对于许多炎症性疾病的发病机理至关重要，主要通过p55肿瘤坏死因子受体1（TNFR1）作用。生物学剂已成功地针对类风湿关节炎和其他炎症性疾病的TNFR1。我们正在与NHGRI的遗传学和基因组分支合作，以了解TNF受体相关周期性综合征（TRAPS）患者的炎症病理生理学，这是一种与TNFR1中显性突变相关的遗传自身炎症性疾病。 TNFR1突变如何易于炎症。用生物学剂阻断TNF仅在治疗陷阱症状方面有效地有效。我们发现，与陷阱相关的TNFR1突变分子错误折叠并积聚在内质网中。在最近的工作中，我们发现TNFR1蛋白会在捕获陷阱内积聚在患者外周血单核细胞（PBMC）和具有两个独立陷阱相关TNFR1突变的小鼠。突变TNFR1蛋白的存在特异性激活了MAP-激酶途径中的信号传导，而NF-KB激活不受影响。来自杂合TNFR1突变小鼠的细胞表现出促炎性细胞因子的产生升高，对脂多糖（LPS，LPS）的全身性超敏反应，患者PBMC的陷阱是高剂量LPS​​的过度反应。相比之下，纯合TNFR1突变小鼠对LPS诱导的败血性休克有抗性，类似于TNFR1缺乏小鼠。 MAP激酶的过度激活和增强的炎症信号传导取决于活性氧的线粒体产生，将线粒体ROS鉴定为陷阱中可能的治疗靶标。这些结果为陷阱的发病机理提供了新的启示，并确定了陷阱和其他炎症性疾病中抗炎治疗的新型策略。 这些研究刺激了有关代谢和炎症的进一步研究。 我们研究了AMP活化激酶（AMPK）作为甲氨蝶呤的靶标的潜在作用。 我们还研究了营养与光提示巨噬细胞和肝细胞基因表达以及对LPS诱导败血症的敏感性的影响。我们发现，对致命LPS挑战的敏感性受喂养而不是光周期的调节，而在觉醒时遭受了较高的死亡率，但在受到时间限制的小鼠中逆转逆转。喂养败血症的喂养易感性不伴随着炎性细胞因子的产生增加，内源性糖皮质激素或与饥饿相关的酮与死亡率无关。相反，LPS给药后的低血糖与死亡率相关，这与最近的结果相一致，表明维持血清葡萄糖是鼠败血症模型和临床败血症早期死亡率的关键生存因子。我们发现，使用关键的昼夜节律基因BMAL1以肝脏内部的方式调节对败血症的喂养调节易感性，使用该基因在肝脏中有条件删除的小鼠。

项目成果

Wishing away inflammation? New links between serotonin and TNF signaling.

希望消除炎症？

• DOI: 10.1124/mi.9.6.5
• 发表时间: 2009
• 期刊: Molecular interventions
• 作者: Pelletier,Martin;Siegel,RichardM
• 通讯作者: Siegel,RichardM

TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in multiple sclerosis.

• DOI: 10.1038/nature11307
• 发表时间: 2012-08-23
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Gregory, Adam P.;Dendrou, Calliope A.;Attfield, Kathrine E.;Haghikia, Aiden;Xifara, Dionysia K.;Butter, Falk;Poschmann, Gereon;Kaur, Gurman;Lambert, Lydia;Leach, Oliver A.;Proemel, Simone;Punwani, Divya;Felce, James H.;Davis, Simon J.;Gold, Ralf;Nielsen, Finn C.;Siegel, Richard M.;Mann, Matthias;Bell, John I.;McVean, Gil;Fugger, Lars
• 通讯作者: Fugger, Lars

New tricks from an old dog: mitochondrial redox signaling in cellular inflammation.

• DOI: 10.1016/j.smim.2013.01.002
• 发表时间: 2012-12
• 期刊: Seminars in immunology
• 影响因子: 7.8
• 作者: Pelletier M;Lepow TS;Billingham LK;Murphy MP;Siegel RM
• 通讯作者: Siegel RM