Autophagy contributes to inflammation in patients with TNFR-associated periodic syndrome (TRAPS).

Abstract

OBJECTIVES:

Tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is caused by TNFRSF1A mutations, known to induce intracellular retention of the TNFα receptor 1 (TNFR1) protein, defective TNFα-induced apoptosis, and production of reactive oxygen species. As downregulation of autophagy, the main cellular pathway involved in insoluble aggregate elimination, has been observed to increase the inflammatory response, we investigated whether it plays a role in TRAPS pathogenesis.

METHODS:

The possible link between TNFRSF1A mutations and inflammation in TRAPS was studied in HEK-293T cells, transfected with expression constructs for wild-type and mutant TNFR1 proteins, and in monocytes derived from patients with TRAPS, by investigating autophagy function, NF-κB activation and interleukin (IL)-1β secretion.

RESULTS:

We found that autophagy is responsible for clearance of wild-type TNFR1, but when TNFR1 is mutated, the autophagy process is defective, probably accounting for mutant TNFR1 accumulation as well as TRAPS-associated induction of NF-κB activity and excessive IL-1β secretion, leading to chronic inflammation. Autophagy inhibition due to TNFR1 mutant proteins can be reversed, as demonstrated by the effects of the antibiotic geldanamycin, which was found to rescue the membrane localisation of mutant TNFR1 proteins, reduce their accumulation and counteract the increased inflammation by decreasing IL-1β secretion.

CONCLUSIONS:

Autophagy appears to be an important mechanism in the pathogenesis of TRAPS, an observation that provides a rationale for the most effective therapy in this autoinflammatory disorder. Our findings also suggest that autophagy could be proposed as a novel therapeutic target for TRAPS and possibly other similar diseases.

• Authors: Tiziana Bachetti, Sabrina Chiesa, Patrizio Castagnola, Daniele Bani, Eleonora Di Zanni, Alessia Omenetti, Andrea D'Osualdo, Alessandro Fraldi, Andrea Ballabio, Roberto Ravazzolo, Alberto Martini, Marco Gattorno, Isabella Ceccherini
• Journal: Annals of the rheumatic diseases (Ann Rheum Dis) Vol. 72 Issue 6 Pg. 1044-52 (Jun 2013) ISSN: 1468-2060 [Electronic] England
• PMID: 23117241 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• IL1B protein, human
• Interleukin-1beta
• NF-kappa B
• Receptors, Tumor Necrosis Factor, Type I
• TNFRSF1A protein, human

Topics

• Adolescent
• Adult
• Autophagy (genetics, physiology)
• Case-Control Studies
• Child
• Child, Preschool
• HEK293 Cells
• Hereditary Autoinflammatory Diseases (genetics)
• Humans
• Interleukin-1beta (metabolism)
• Middle Aged
• NF-kappa B (physiology)
• Receptors, Tumor Necrosis Factor, Type I (genetics, physiology)
• Syndrome