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
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