title: Interleukin-23 is critical for full-blown expression of a non-autoimmune destructive arthritis and regulates interleukin-17A and RORgammat in gammadelta T cells.
abstract: BACKGROUND
  Interleukin (IL)-23 is essential for the development of various experimental autoimmune models. However, the role of IL-23 in non-autoimmune experimental arthritis remains unclear. Here, we examined the role of IL-23 in the non-autoimmune antigen-induced arthritis (AIA) model. In addition, the regulatory potential of IL-23 in IL-17A and retinoic acid-related orphan receptor gamma t (RORgammat) expression in CD4+ and TCRgammadelta+ T cells was evaluated systemically as well as at the site of inflammation.
  
  
  METHODS
  Antigen-induced arthritis was induced in wild-type, IL-23p19-deficient and IL-17 Receptor A - knockout mice. At different time points, synovial cytokine and chemokine expression was measured. At days 1 and 7 of AIA, splenocytes and joint-infiltrating cells were isolated and analyzed for intracellular IL-17A and interferon (IFN)-gamma ex-vivo by flow cytometry. In splenic CD4+ and TCRgammadelta+ T cells gene expression was quantified by flow cytometry and quantitative PCR.
  
  
  RESULTS
  IL-23 was critical for full-blown AIA. Lack of IL-23 did not prevent the onset of joint inflammation but stopped the progression to a destructive synovitis. IL-23 regulated IL-17A expression in CD4+ T cells in the spleen. Of note, IL-17A and IFN-gamma expression was reduced in CD4+ T cells in the inflamed joints of IL-23p19-deficient mice. Interestingly, IL-23 was also critical for the induction of IL-17A and RORgammat but not IFN-gamma in TCRgammadelta+ T cells in the inflamed joints. The importance of the IL-23/IL-17 axis was further confirmed using IL-17 Receptor A knockout mice showing significantly milder AIA compared to control mice, with a disease course comparable to that of IL-23p19-deficient mice.
  
  
  CONCLUSIONS
  These data show that IL-23 is critical for full-blown expression of a non-autoimmune destructive arthritis and regulates the proportion of IL-17A and IFN-gamma-positive CD4+ T cells at the site of inflammation. Furthermore, IL-23 regulates IL-17A and RORgammat expression in TCRgammadelta T cells in arthritis. These findings indicate that regulating the IL-23 pathway may have therapeutic potential in non-autoimmune arthritis.
authors.affiliation: Department of Rheumatology, Erasmus Medical Center Rotterdam, Dr, Molewaterplein 50, Rotterdam, 3015 GE, the Netherlands. f.cornelissen@erasmusmc.nl
authors.forename: Ferry
authors.initials: F
authors.lastname: Cornelissen
authors.forename: Adriana Mc
authors.initials: AM
authors.lastname: Mus
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Asmawidjaja
authors.forename: Jan Piet
authors.initials: JP
authors.lastname: van Hamburg
authors.forename: Joel
authors.initials: J
authors.lastname: Tocker
authors.forename: Erik
authors.initials: E
authors.lastname: Lubberts
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002469:Cell Separation; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D053759:Interleukin-23 / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000276:immunology / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D016692:Receptors, Antigen, T-Cell, gamma-delta; D007371:Interferon-gamma