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

Ann Rheum Dis 2013 Jun 31;72(6):1044-52. Epub 2012 Oct 31.

Laboratory of Molecular Genetics, Giannina Gaslini Institute, Genoa, Italy.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1136/annrheumdis-2012-201952DOI Listing
June 2013
15 Reads

Publication Analysis

Top Keywords

mutant tnfr1
12
tnfr1 proteins
8
autophagy
8
tnfrsf1a mutations
8
periodic syndrome
8
syndrome traps
8
traps
7
tnfr1
7
wild-type tnfr1
4
tnfr1 tnfr1
4
tnfr1 mutated
4
nf-κb activity
4
clearance wild-type
4
activity excessive
4
secretionresults autophagy
4
autophagy responsible
4
responsible clearance
4
mutated autophagy
4
induction nf-κb
4
defective accounting
4

Similar Publications