Mutations in the type 1 TNF receptor (TNFR1) cause the autoinflammatory disorder TNF receptor-associated periodic syndrome (TRAPS), a disease characterized by recurrent fevers with inflammation. TRAPS-associated mutations in TNFR1 cause misfolding, retention in the ER, and loss of function as a conventional receptor, but instead initiate an intracellular signaling cascade that results in hyper-responsiveness to innate stimuli. Using mice engineered to have TRAPS-associated mutations in TNFR1, we examined the contents of peritoneal lavage fluid after intraperitoneal LPS injection in order to identify the pathogenic cell type. TNFR1 mutant mice have increased monocyte/macrophage infiltrates when compared to wild-type mice, but a similar number of recruited neutrophils. In mixed marrow chimeras, wild-type and TNFR1 mutant neutrophils were recruited similarly into the peritoneum after LPS injection, suggesting that there is no cell-intrinsic predisposition of TNFR1 mutant neutrophils to accumulate at sites of inflammation. In support of this, neutrophils from TRAPS patients and healthy donors migrate similarly in response to CXCL8. In contrast, we found that murine peritoneal macrophages from TNFR1 mutant mice produce higher amounts of two potent chemokines, CXCL1 and CXCL2, in response to LPS in vitro. These results suggest that enhanced chemokine secretion by monocytes, rather than hyper-responsiveness of neutrophils to these stimuli, is critical to the pathogenesis of TRAPS.
- Copyright © 2011 by The American Association of Immunologists, Inc.