title: Evidence that autophagy, but not the unfolded protein response, regulates the expression of IL-23 in the gut of patients with ankylosing spondylitis and subclinical gut inflammation.
abstract: OBJECTIVE
  Interleukin (IL)-23 has been implicated in the pathogenesis of ankylosing spondylitis (AS). The aim of the study was to clarify the mechanisms underlying the increased IL-23 expression in the gut of AS patients.
  
  
  METHODS
  Consecutive gut biopsies from 30 HLA-B27(+) AS patients, 15 Crohn's disease (CD) patients and 10 normal subjects were obtained. Evidence for HLA-B27 misfolding was studied. Unfolded protein response (UPR) and autophagy were assessed by RT-PCR and immunohistochemistry. The contribution of UPR and autophagy in the regulation of IL-23 expression was evaluated in in vitro experiments on isolated lamina propria mononuclear cells (LPMCs).
  
  
  RESULTS
  Intracellular colocalisation of SYVN1 and FHCs but not a significant overexpression of UPR genes was observed in the gut of AS patients. Conversely, upregulation of the genes involved in the autophagy pathway was observed in the gut of AS and CD patients. Immunohistochemistry showed an increased expression of LC3II, ATG5 and ATG12 but not of SQSTM1 in the ileum of AS and CD patients. LC3II was expressed among infiltrating mononuclear cells and epithelial cells resembling Paneth cells (PC) and colocalised with ATG5 in AS and CD. Autophagy but not UPR was required to modulate the expression of IL-23 in isolated LPMCs of AS patients with chronic gut inflammation, CD patients and controls.
  
  
  CONCLUSIONS
  Our data suggest that HLA-B27 misfolding occurs in the gut of AS patients and is accompanied by activation of autophagy rather than a UPR. Autophagy appears to be associated with intestinal modulation of IL-23 in AS.
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università di Palermo, Palermo, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ciccia
authors.affiliation: Anatomia Patologica, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
authors.forename: Antonina
authors.initials: A
authors.lastname: Accardo-Palumbo
authors.affiliation: Anatomia Patologica, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
authors.forename: Aroldo
authors.initials: A
authors.lastname: Rizzo
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università di Palermo, Palermo, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Guggino
authors.affiliation: Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università di Palermo, Palermo, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Raimondo
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università di Palermo, Palermo, Italy.
authors.forename: AnnaRita
authors.initials: A
authors.lastname: Giardina
authors.affiliation: Anatomia Patologica, Ospedali Riuniti Villa Sofia-Cervello, Palermo, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cannizzaro
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, Maryland, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Colbert
authors.affiliation: Dipartimento di Biopatologia e Biotecnologie Mediche e Forensi, Università di Palermo, Palermo, Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Alessandro
authors.affiliation: Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Università di Palermo, Palermo, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Triolo
mesh_terms: D000328:Adult; D000368:Aged; D001343:Autophagy / Q000276:immunology*; D001706:Biopsy; D003424:Crohn Disease / Q000276:immunology / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000276:immunology; D015796:HLA-B27 Antigen / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007079:Ileitis / Q000276:immunology* / Q000473:pathology; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000276:immunology*; D007422:Intestines / Q000276:immunology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000276:immunology / Q000473:pathology; D017510:Protein Folding; D013167:Spondylitis, Ankylosing / Q000276:immunology* / Q000473:pathology; D056811:Unfolded Protein Response / Q000276:immunology*; D055815:Young Adult
chemical_list: D015796:HLA-B27 Antigen; C508840:IL23A protein, human; D053760:Interleukin-23 Subunit p19
keywords: Cytokines; Inflammation; Spondyloarthritis