Evaluation of the effects of disease-causing mutations in type I TNF receptor (TNFR1) on neutrophil responses (140.8)

Abstract

Abstract Mutations in the type 1 TNF receptor (TNFR1) cause an autosomal-dominantly inherited autoinflammatory disorder called TNF receptor-associated periodic syndrome (TRAPS). The disease is characterized by recurrent fevers with abdominal pain, migratory rash and inflammation. Patients also develop serositis, including peritonitis, as a manifestation of disease flares. TRAPS-associated mutant receptors do not traffic to the cell surface and accumulate in the endoplasmic reticulum, which may lead to abnormal TNF-independent receptor signaling and sustained inflammation. We examined the contents of peritoneal lavage fluid after intraperitoneal injection of LPS in TNFR1 mutant mice. Interestingly, heterozygous TNFR1 mutant mice had increased neutrophil infiltrates into the peritoneal cavity after LPS injection. We have investigated whether the exaggerated infiltration of neutrophils in mice with TNFR1 mutations is due to an intrinsic neutrophil abnormality or the release of more neutrophil-attracting chemokines by macrophages. We have performed chemotaxis experiments using neutrophils isolated from TRAPS patients as well as TNFR1 mutant mice, and measured the migratory responses of neutrophils toward chemoattractants and macrophage-derived supernatants. These results will provide insights into whether the intracellularly retained mutant TNFR1 may function to enhance local neutrophil accumulation in response to inflammatory stimuli in a cell autonomous manner.