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 MAP-Kinase signaling, 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.

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Project End
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Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$568,218
Indirect Cost
Name
National Institute of Arthritis and Musculoskeletal and Skin Diseases
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Type
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Pelletier, Martin; Billingham, Leah K; Ramaswamy, Madhu et al. (2014) Extracellular flux analysis to monitor glycolytic rates and mitochondrial oxygen consumption. Methods Enzymol 542:125-49