Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome

Abstract

TNF, acting through p55 tumor necrosis factor receptor 1 (TNFR1), contributes to the pathogenesis of many inflammatory diseases. TNFR-associated periodic syndrome (TRAPS, OMIM 142680) is an autosomal dominant autoinflammatory disorder characterized by prolonged attacks of fevers, peritonitis, and soft tissue inflammation. TRAPS is caused by missense mutations in the extracellular domain of TNFR1 that affect receptor folding and trafficking. These mutations lead to loss of normal function rather than gain of function, and thus the pathogenesis of TRAPS is an enigma. Here we show that mutant TNFR1 accumulates intracellularly in peripheral blood mononuclear cells of TRAPS patients and in multiple cell types from two independent lines of knockin mice harboring TRAPSassociated TNFR1 mutations. Mutant TNFR1 did not function as a surface receptor for TNF but rather enhanced activation of MAPKs and secretion of proinflammatory cytokines upon stimulation with LPS. Enhanced inflammation depended on autocrine TNF secretion and WT TNFR1 in mouse and human myeloid cells but not in fibroblasts. Heterozygous TNFR1-mutant mice were hypersensitive to LPS-induced septic shock, whereas homozygous TNFR1-mutant mice resembled TNFR1-deficient mice and were resistant to septic shock. Thus WT and mutant TNFR1 act in concert from distinct cellular locations to potentiate inflammation in TRAPS. These findings establish a mechanism of pathogenesis in autosomal dominant diseases where full expression of the disease phenotype depends on functional cooperation between WT and mutant proteins and also may explain partial responses of TRAPS patients to TNF blockade. autoinflammatory disease | genetic disease

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

“…Mutations in the CRDs are often associated with severe disease, such as the T50M and C88R mutations, whereas other mutations may be less severe; for example, R92Q and P46L variants may be associated with mild disease or can be clinically asymptomatic, and have a 1-5% prevalence in the population [13]. Although the inflammatory features of disease suggests that TRAPS-linked TNFR1 mutations should be gain-of-function, knock-in mice homozygous for TRAPS mutations do not manifest a TRAPS disease phenotype, but are resistant to LPS-induced septic shock [14]. In keeping with these reports the majority of TRAPS-causing mutations observed to date are heterozygous, suggesting that expression of both the functional and mutant receptor is required for TRAPS pathogenesis [9].…”

Immunotherapeutic Biologic Agents to Treat Autoinflammatory Diseases

“…In addition, impaired mutant TNF receptor shedding occurs. Mutant 55 kDa TNF receptor 1a surfacebased receptors appear to have several defects: abnormal protein-folding responses, binding TNF less effectively causing defective TNF-associated apoptosis, prolongation of immune responses to non-mutated receptor-bound TNF, and uncontrolled downstream signaling [22]. Abnormal p55 receptors shed in TRAPS are unable to serve as naturally occurring decoys for circulating TNF [20].…”

Role of tumour necrosis factor (TNF)-α and TNFRSF1A R92Q mutation in the pathogenesis of TNF receptor-associated periodic syndrome and multiple sclerosis

“…The mutant receptors self-interact and trigger an inflammatory response [38,41,43]. They are also unable to activate the TNF-a-induced NF-kB transcription pathway, which leads to a reduction in apoptosis [44] and prolonged survival of the activated inflammatory cells, contributing to the inflammatory phenotype of the disease [45,46].…”

“…The mutations affecting cysteine residues (structural mutations) [41] cause changes in the three-dimensional structure of the TNFR1 ectodomain, leading to accumulation of the mutated receptor in the endoplasmic reticulum [42]. The mutant receptors self-interact and trigger an inflammatory response [38,41,43].…”