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.