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- Title
RORγt inhibition ameliorates IL-23 driven experimental psoriatic arthritis by predominantly modulating γδ-T cells.
- Authors
Mortier, Céline; Gracey, Eric; Coudenys, Julie; Manuello, Teddy; Decruy, Tine; Maelegheer, Margaux; Stappers, Flore; Gilis, Elisabeth; Gaublomme, Djoere; Hoorebeke, Luc Van; Welden, Sophie Van; Ambler, Catherine; Hegen, Martin; Symanowicz, Peter; Steyn, Stefan; Berstein, Gabriel; Elewaut, Dirk; Venken, Koen
- Abstract
Objective Divergent therapeutic outcomes on different disease domains have been noted with IL-23 and IL-17A-blockade in PsA. Therefore, elucidating the role of RORγt, the master regulator of type 17 immune responses, is of potential therapeutic interest. To this end, RORγt inhibition was assessed in combined skin, joint and gut inflammation in vivo , using a PsA model. Methods We tested the efficacy of a RORγt antagonist in B10.RIII mice challenged with systemic overexpression of IL-23 by hydrodynamic injection of IL-23 enhanced episomal vector (IL-23 EEV). Clinical outcomes were evaluated by histopathology. Bone density and surface erosions were examined using micro-computed tomography. Cytokine production was measured in serum and by intracellular flow cytometry. Gene expression in PsA-related tissues was analysed by qPCR. Results RORγt-blockade significantly ameliorated psoriasis, peripheral arthritis and colitis development in IL-23 EEV mice (improvement of clinical scores and weight loss respectively by 91.8%, 58.2% and 7.0%, P < 0.001), in line with profound suppression of an enhanced type IL-17 immune signature in PsA-affected tissues. Moreover, inflammation-induced bone loss and bone erosions were reduced (P < 0.05 in calcaneus, P < 0.01 in tibia). Sustained IL-23 overexpression resulted in only mild signs of sacroiliitis. Gamma-delta (γδ)-T cells, the dominant source of T cell-derived IL-17A and IL-22, were expanded during IL-23 overexpression, and together with Th17 cells, clearly countered by RORγt inhibition (P < 0.001). Conclusion RORγt-blockade shows therapeutic efficacy in a preclinical PsA model with protection towards extra-musculoskeletal manifestations, reflected by a clear attenuation of type 17 cytokine responses by γδ-T cells and Th17 cells.
- Subjects
PSORIATIC arthritis; BIOLOGICAL models; INTERLEUKINS; CYTOKINES; FLOW cytometry; KRUSKAL-Wallis Test; STATISTICS; IN vivo studies; ANIMAL experimentation; ONE-way analysis of variance; MANN Whitney U Test; ANTIRHEUMATIC agents; T-test (Statistics); PEARSON correlation (Statistics); RESEARCH funding; GENE expression profiling; T cells; BONE density; COMPUTED tomography; POLYMERASE chain reaction; DATA analysis software; DATA analysis; MICE; PHARMACODYNAMICS; CHEMICAL inhibitors
- Publication
Rheumatology, 2023, Vol 62, Issue 9, p3169
- ISSN
1462-0324
- Publication type
Article
- DOI
10.1093/rheumatology/kead022