TY - JOUR
T1 - Interleukin-23 is critical for full-blown expression of a non-autoimmune destructive arthritis and regulates interleukin-17A and RORγt in γδ T cells
AU - Cornelissen, Ferry
AU - Mus, Adriana M.C.
AU - Asmawidjaja, Patrick S.
AU - van Hamburg, Jan P.
AU - Tocker, Joel
AU - Lubberts, Erik
N1 - Funding Information: We would like to thank people from the EDC Animal Facility (Erasmus Medical Center Rotterdam) for technical assistance at various stages of the project. This project was financially supported by a grant from Erasmus Medical Center, Rotterdam, the Netherlands. We would like to thank Dr. R.W. Hendriks and Dr. A. Boonstra for critically reading the manuscript and E. de Haas for technical assistance with the FACS-sorting experiments.
PY - 2009/12/17
Y1 - 2009/12/17
N2 - Introduction: 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 (RORγt) expression in CD4+ and TCRγδ+ 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)-γ ex-vivo by flow cytometry. In splenic CD4+ and TCRγδ+ 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-γ 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 RORγt but not IFN-γ in TCRγδ+ 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-γ-positive CD4+ T cells at the site of inflammation. Furthermore, IL-23 regulates IL-17A and RORγt expression in TCRγδ T cells in arthritis. These findings indicate that regulating the IL-23 pathway may have therapeutic potential in non-autoimmune arthritis.
AB - Introduction: 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 (RORγt) expression in CD4+ and TCRγδ+ 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)-γ ex-vivo by flow cytometry. In splenic CD4+ and TCRγδ+ 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-γ 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 RORγt but not IFN-γ in TCRγδ+ 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-γ-positive CD4+ T cells at the site of inflammation. Furthermore, IL-23 regulates IL-17A and RORγt expression in TCRγδ T cells in arthritis. These findings indicate that regulating the IL-23 pathway may have therapeutic potential in non-autoimmune arthritis.
UR - http://www.scopus.com/inward/record.url?scp=77949653393&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/ar2893
DO - https://doi.org/10.1186/ar2893
M3 - Article
C2 - 20017902
SN - 1478-6354
VL - 11
JO - Arthritis Research and Therapy
JF - Arthritis Research and Therapy
IS - 6
M1 - R194
ER -