Intracellular accumulation of mutant TNFR1 potentiates MAP‐Kinase signaling and innate immune responses in the TNF‐receptor associated Periodic Syndrome (TRAPS)

Tumor necrosis factor (TNF) receptor‐associated periodic syndrome (TRAPS) is an autosomal dominant auto‐inflammatory syndrome associated with mutations in the gene that encodes tumor necrosis factor receptor 1 (TNFR1). How these mutations predispose to inflammation is not known. We have previously shown that TRAPS‐related mutant TNFR1 failed to bind TNF or traffic to the cell surface. These mutants exhibited abnormal oligomerization and are retained in the endoplasmic reticulum (ER). In both knock‐in mice and patient PBMC, TRAPS mutant TNFR1 accumulates intracellularly and has a prolonged half‐life. This suggests that intracellular accumulation of mutant TNFR1 is linked to disease in TRAPS. Although cells harboring TRAPS mutant TNFR1 were defective in signaling in response to TNF, MAP kinases were found to be constitutively activated, and stimulation with LPS resulted in prolonged activation of JNK, ERK and p38 kinases with intact NF‐κB activation. These signaling abnormalities led to dramatically increased TNF‐independent production of IL‐6 in cells with one or both mutant TNFR1 alleles. Increased IL‐6 production was dependent on Reactive Oxygen Species, which have been previously been shown to sustain MAPK signaling after TNF treatment. We conclude that intracellular mutant TNFR1 in TRAPS potentiates innate immune signaling through abnormal activation of MAPK and ROS.