TNFR1 in the regulation of autoinflammatory diseases

TNFR1在自身炎症性疾病调节中的作用

• 批准号: 7732840
• 负责人: Richard M Siegel
• 金额: $ 35.37万
• 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/7732840
• 关键词: Affect; Autoimmune Diseases; Autoimmune Process; Cells; Chronic; Complex; Disease; Dose; Endoplasmic Reticulum; Exhibits; Family; Fever; Functional disorder; Genetic; Genomics; Goals; Hypersensitivity; Immune; Immune response; Inflammation; Inflammatory; Knock-in Mouse; Lead; Ligands; Light; Link; Mitogen-Activated Protein Kinases; Mus; Mutant Strains Mice; Mutate; Mutation; Natural Immunity; Numbers; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Production; Proteins; Reagent; Regulation; Resistance; Rheumatoid Arthritis; Septic Shock; Signal Pathway; Signal Transduction; Symptoms; Syndrome; TNF receptor-associated periodic fever syndrome; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Work; cytokine; disease phenotype; human MPP1 protein; human TNF protein; immunoregulation; improved; insight; mutant; novel

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 NIAMS 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 PBMC and knock-in mice harboring two independent TRAPS associated TNFR1 mutations. Presence of the mutant TNFR1 protein specifically MAP-Kinase signaling, while NF-κB activation was not affected. Cells from heterozygous TNFR1 mutant mice exhibited elevated production of pro-inflammatory cytokines and systemic hypersensitivity to 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. These results shed new light on the pathogenesis of TRAPS and establish a novel paradigm where full expression of an autosomal dominant disease phenotype depends on functional cooperation between wild-type and mutant proteins. Blocking signaling pathways that are specifically hyperactivated in TRAPS may synergize with TNF blockade to benefit patients with this periodic fever syndrome. These studies have also revealed that ligand-independent signaling by mutant TNFR1 in the ER can predispose to inflammation, and suggest that under some circumstances, the normal TNFR1 may also signal in this manner. We are generating new reagents to study subcellular localization and formation of signaling complexes by intracellular TNFR1 to better understand this issue

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NIAMS中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（TRAP）患者的炎症病理生理学（TRAPS）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蛋白会在患者PBMC的陷阱内积聚，并在具有两个独立的TNFR1突变的独立陷阱的敲入小鼠中积聚。突变体TNFR1蛋白的存在特异性地图激酶信号传导，而NF-κB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和对LPS的全身性超敏反应，患者PBMC的陷阱对低剂量LPS​​具有超响应性。相反，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。这些结果为陷阱的发病机理提供了新的启示，并建立了一种新的范式，其中常染色体显性疾病表型的完全表达取决于野生型和突变蛋白之间的功能合作。在陷阱中特异性化过度激活的阻塞信号通路可能会与TNF阻滞协同作用，以使该周期性发烧综合征患者受益。 这些研究还表明，ER中突变体TNFR1的非配体独立信号传导可能会易于发炎，并建议在某些情况下，正常TNFR1也可能以这种方式发出信号。我们正在生成新试剂，以研究细胞内TNFR1的亚细胞定位和信号传导复合物的形成，以更好地理解此问题