Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic Rats
ObjectiveIL-17A plays a major role in the pathogenesis of spondyloarthritis (SpA). Here we assessed the impact of inhibition of RAR related orphan receptor-γ (RORC), the key transcription factor controlling IL-17 production, on experimental SpA in HLA-B27 transgenic (tg) rats.MethodsExperimental SpA...
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Frontiers Media S.A.
2021-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.699987/full |
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| author | Melissa N. van Tok Melissa N. van Tok Mohamed Mandour Mohamed Mandour Joseph Wahle Mark E. Labadia Marleen G. H. van de Sande Marleen G. H. van de Sande Gerald Nabozny Dominique L. Baeten Dominique L. Baeten Leonie M. van Duivenvoorde Leonie M. van Duivenvoorde |
| author_facet | Melissa N. van Tok Melissa N. van Tok Mohamed Mandour Mohamed Mandour Joseph Wahle Mark E. Labadia Marleen G. H. van de Sande Marleen G. H. van de Sande Gerald Nabozny Dominique L. Baeten Dominique L. Baeten Leonie M. van Duivenvoorde Leonie M. van Duivenvoorde |
| author_sort | Melissa N. van Tok |
| collection | DOAJ |
| description | ObjectiveIL-17A plays a major role in the pathogenesis of spondyloarthritis (SpA). Here we assessed the impact of inhibition of RAR related orphan receptor-γ (RORC), the key transcription factor controlling IL-17 production, on experimental SpA in HLA-B27 transgenic (tg) rats.MethodsExperimental SpA was induced by immunization of HLA-B27 tg rats with heat-inactivated Mycobacterium tuberculosis. Splenocytes obtained at day 7, 14 and 21 after immunization were restimulated ex vivo to assess the induction of pro-inflammatory cytokines. Rats were then prophylactically treated with a RORC inhibitor versus vehicle control. The biologic effect of RORC inhibition was assessed by pro-inflammatory cytokine expression in draining lymph nodes. Arthritis and spondylitis were monitored clinically, and the degree of peripheral and axial inflammation, destruction and new bone formation was confirmed by histology.ResultsEx vivo mRNA and protein analyses revealed the rapid and selective induction of IL-17A and IL-22 production by a variety of lymphocyte subsets upon disease induction in HLA-B27 tg rats. Prophylactic RORC inhibition in vivo suppressed the expression of IL-17A, IL17F, and IL-22 without affecting the expression of other T helper cell subset related genes. This biological effect did not translate into clinical efficacy as RORC inhibition significantly accelerated the onset of arthritis and spondylitis, and aggravated the clinical severity of arthritis. This worsening of experimental SpA was confirmed by histopathological demonstration of increased inflammation, destruction, and new bone formation.ConclusionDespite a significant suppression of the IL-17 axis, RORC inhibitor treatment accelerates and aggravates experimental SpA in the HLA-B27 tg rat model. |
| first_indexed | 2024-12-17T23:53:52Z |
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| id | doaj.art-8927b65231f14e34b3bb4c1d8e654936 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-17T23:53:52Z |
| publishDate | 2021-09-01 |
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| series | Frontiers in Immunology |
| spelling | doaj.art-8927b65231f14e34b3bb4c1d8e6549362022-12-21T21:28:08ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-09-011210.3389/fimmu.2021.699987699987Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic RatsMelissa N. van Tok0Melissa N. van Tok1Mohamed Mandour2Mohamed Mandour3Joseph Wahle4Mark E. Labadia5Marleen G. H. van de Sande6Marleen G. H. van de Sande7Gerald Nabozny8Dominique L. Baeten9Dominique L. Baeten10Leonie M. van Duivenvoorde11Leonie M. van Duivenvoorde12Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam University Medical Centers (UMC), Location Academic Medical Center, University of Amsterdam, Amsterdam, NetherlandsDepartment of Experimental Immunology, Infection and Immunity Institute, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Clinical Immunology and Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam University Medical Centers (UMC), Location Academic Medical Center, University of Amsterdam, Amsterdam, NetherlandsDepartment of Experimental Immunology, Infection and Immunity Institute, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, NetherlandsImmunology and Respiratory Diseases, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, United StatesImmunology and Respiratory Diseases, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, United StatesDepartment of Clinical Immunology and Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam University Medical Centers (UMC), Location Academic Medical Center, University of Amsterdam, Amsterdam, NetherlandsDepartment of Experimental Immunology, Infection and Immunity Institute, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, NetherlandsImmunology and Respiratory Diseases, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, United StatesDepartment of Clinical Immunology and Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam University Medical Centers (UMC), Location Academic Medical Center, University of Amsterdam, Amsterdam, NetherlandsDepartment of Experimental Immunology, Infection and Immunity Institute, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Clinical Immunology and Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam University Medical Centers (UMC), Location Academic Medical Center, University of Amsterdam, Amsterdam, NetherlandsDepartment of Experimental Immunology, Infection and Immunity Institute, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, NetherlandsObjectiveIL-17A plays a major role in the pathogenesis of spondyloarthritis (SpA). Here we assessed the impact of inhibition of RAR related orphan receptor-γ (RORC), the key transcription factor controlling IL-17 production, on experimental SpA in HLA-B27 transgenic (tg) rats.MethodsExperimental SpA was induced by immunization of HLA-B27 tg rats with heat-inactivated Mycobacterium tuberculosis. Splenocytes obtained at day 7, 14 and 21 after immunization were restimulated ex vivo to assess the induction of pro-inflammatory cytokines. Rats were then prophylactically treated with a RORC inhibitor versus vehicle control. The biologic effect of RORC inhibition was assessed by pro-inflammatory cytokine expression in draining lymph nodes. Arthritis and spondylitis were monitored clinically, and the degree of peripheral and axial inflammation, destruction and new bone formation was confirmed by histology.ResultsEx vivo mRNA and protein analyses revealed the rapid and selective induction of IL-17A and IL-22 production by a variety of lymphocyte subsets upon disease induction in HLA-B27 tg rats. Prophylactic RORC inhibition in vivo suppressed the expression of IL-17A, IL17F, and IL-22 without affecting the expression of other T helper cell subset related genes. This biological effect did not translate into clinical efficacy as RORC inhibition significantly accelerated the onset of arthritis and spondylitis, and aggravated the clinical severity of arthritis. This worsening of experimental SpA was confirmed by histopathological demonstration of increased inflammation, destruction, and new bone formation.ConclusionDespite a significant suppression of the IL-17 axis, RORC inhibitor treatment accelerates and aggravates experimental SpA in the HLA-B27 tg rat model.https://www.frontiersin.org/articles/10.3389/fimmu.2021.699987/fullspondyloarthritisIL-17ARORCIL-22HLA-B27 transgenic rats |
| spellingShingle | Melissa N. van Tok Melissa N. van Tok Mohamed Mandour Mohamed Mandour Joseph Wahle Mark E. Labadia Marleen G. H. van de Sande Marleen G. H. van de Sande Gerald Nabozny Dominique L. Baeten Dominique L. Baeten Leonie M. van Duivenvoorde Leonie M. van Duivenvoorde Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic Rats Frontiers in Immunology spondyloarthritis IL-17A RORC IL-22 HLA-B27 transgenic rats |
| title | Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic Rats |
| title_full | Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic Rats |
| title_fullStr | Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic Rats |
| title_full_unstemmed | Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic Rats |
| title_short | Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic Rats |
| title_sort | paradoxical augmentation of experimental spondyloarthritis by rorc inhibition in hla b27 transgenic rats |
| topic | spondyloarthritis IL-17A RORC IL-22 HLA-B27 transgenic rats |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.699987/full |
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