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Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic Rats

OBJECTIVE: IL-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. METHODS: Experimenta...

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Autores principales: van Tok, Melissa N., Mandour, Mohamed, Wahle, Joseph, Labadia, Mark E., van de Sande, Marleen G. H., Nabozny, Gerald, Baeten, Dominique L., van Duivenvoorde, Leonie M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451327/
https://www.ncbi.nlm.nih.gov/pubmed/34552583
http://dx.doi.org/10.3389/fimmu.2021.699987
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author van Tok, Melissa N.
Mandour, Mohamed
Wahle, Joseph
Labadia, Mark E.
van de Sande, Marleen G. H.
Nabozny, Gerald
Baeten, Dominique L.
van Duivenvoorde, Leonie M.
author_facet van Tok, Melissa N.
Mandour, Mohamed
Wahle, Joseph
Labadia, Mark E.
van de Sande, Marleen G. H.
Nabozny, Gerald
Baeten, Dominique L.
van Duivenvoorde, Leonie M.
author_sort van Tok, Melissa N.
collection PubMed
description OBJECTIVE: IL-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. METHODS: Experimental 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. RESULTS: Ex 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. CONCLUSION: Despite a significant suppression of the IL-17 axis, RORC inhibitor treatment accelerates and aggravates experimental SpA in the HLA-B27 tg rat model.
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spelling pubmed-84513272021-09-21 Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic Rats van Tok, Melissa N. Mandour, Mohamed Wahle, Joseph Labadia, Mark E. van de Sande, Marleen G. H. Nabozny, Gerald Baeten, Dominique L. van Duivenvoorde, Leonie M. Front Immunol Immunology OBJECTIVE: IL-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. METHODS: Experimental 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. RESULTS: Ex 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. CONCLUSION: Despite a significant suppression of the IL-17 axis, RORC inhibitor treatment accelerates and aggravates experimental SpA in the HLA-B27 tg rat model. Frontiers Media S.A. 2021-09-06 /pmc/articles/PMC8451327/ /pubmed/34552583 http://dx.doi.org/10.3389/fimmu.2021.699987 Text en Copyright © 2021 van Tok, Mandour, Wahle, Labadia, van de Sande, Nabozny, Baeten and van Duivenvoorde https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
van Tok, Melissa N.
Mandour, Mohamed
Wahle, Joseph
Labadia, Mark E.
van de Sande, Marleen G. H.
Nabozny, Gerald
Baeten, Dominique L.
van Duivenvoorde, Leonie M.
Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in 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 Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451327/
https://www.ncbi.nlm.nih.gov/pubmed/34552583
http://dx.doi.org/10.3389/fimmu.2021.699987
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