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Autophagy contributes to inflammation in patients with TNFR-associated periodic syndrome (TRAPS)
  1. Tiziana Bachetti1,
  2. Sabrina Chiesa2,
  3. Patrizio Castagnola3,
  4. Daniele Bani4,
  5. Eleonora Di Zanni1,
  6. Alessia Omenetti2,
  7. Andrea D'Osualdo5,
  8. Alessandro Fraldi6,
  9. Andrea Ballabio6,7,8,9,
  10. Roberto Ravazzolo1,10,
  11. Alberto Martini2,10,
  12. Marco Gattorno2,
  13. Isabella Ceccherini1
  1. 1Laboratory of Molecular Genetics, Giannina Gaslini Institute, Genoa, Italy
  2. 22nd Pediatric Division, Lab Immunology & Rheumatic Diseases, G Gaslini Inst, Genoa, Italy
  3. 3IRCCS—AOU San Martino, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy
  4. 4Department of Anatomy, Histology & Forensic Medicine, Sect Histology, University of Florence, Firenze, Italy
  5. 5Sanford-Burnham Medical Research Institute, La Jolla, California, USA
  6. 6Telethon Institute of Genetics and Medicine (TIGEM), Naples, Italy
  7. 7Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  8. 8Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, Texas, USA
  9. 9Medical Genetics—Department of Pediatrics, Federico II University, Naples, Italy
  10. 10Department of Pediatrics, University of Genoa, Genoa, Italy
  1. Correspondence to Dr Isabella Ceccherini, Laboratorio Genetica Molecolare, Istituto G Gaslini, Via G Gaslini 5-Genova 16148, Italy; isa.c{at}unige.it

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.

  • Cytokines
  • Fever Syndromes
  • Inflammation

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