title: Autophagy contributes to inflammation in patients with TNFR-associated periodic syndrome (TRAPS).
abstract: OBJECTIVE
  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.affiliation: Laboratory of Molecular Genetics, Giannina Gaslini Institute, Genoa, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bachetti
authors.forename: Sabrina
authors.initials: S
authors.lastname: Chiesa
authors.forename: Patrizio
authors.initials: P
authors.lastname: Castagnola
authors.forename: Daniele
authors.initials: D
authors.lastname: Bani
authors.forename: Eleonora
authors.initials: E
authors.lastname: Di Zanni
authors.forename: Alessia
authors.initials: A
authors.lastname: Omenetti
authors.forename: Andrea
authors.initials: A
authors.lastname: D'Osualdo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fraldi
authors.forename: Andrea
authors.initials: A
authors.lastname: Ballabio
authors.forename: Roberto
authors.initials: R
authors.lastname: Ravazzolo
authors.forename: Alberto
authors.initials: A
authors.lastname: Martini
authors.forename: Marco
authors.initials: M
authors.lastname: Gattorno
authors.forename: Isabella
authors.initials: I
authors.lastname: Ceccherini
mesh_terms: D000293:Adolescent; D000328:Adult; D001343:Autophagy / Q000235:genetics* / Q000502:physiology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D057809:HEK293 Cells; D056660:Hereditary Autoinflammatory Diseases / Q000235:genetics*; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics* / Q000502:physiology; D013577:Syndrome
chemical_list: C508585:IL1B protein, human; D053583:Interleukin-1beta; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; C506235:TNFRSF1A protein, human
keywords: Cytokines; Fever Syndromes; Inflammation