RORγt inhibition ameliorates IL-23 driven experimental psoriatic arthritis by predominantly modulating γδ-T cells

Abstract

Objective Divergent therapeutic outcomes on different disease domains have been noted with interleukin (IL)-23 and IL-17A-blockade in psoriatic arthritis (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.

Gut Inflammation in Axial Spondyloarthritis Patients is Characterized by a Marked Type 17 Skewed Mucosal Innate‐like T Cell Signature

“…RORγt levels in peripheral blood were equally completely restored. This indicates that RORγt is responsive to anti-tumor necrosis factor therapy, which is not unexpected because IL-17-TNF dual-producing cells have been identified in rheumatic diseases (46) and were countered by RORγt inhibition in experimental SpA (40). Intriguingly, RORγt levels were also reduced upon NSAID administration, which has also been reported in other studies (47,48), indicating a general antiinflammatory effect.…”

“…Likewise, RORγt inhibition showed promising results in preclinical models of IBD (44,45). Strikingly, the RORγt antagonist countered the systemic expansion of γδ‐T cells, which were the major producers of IL‐17 (40). In line with these results, we observed that the observed increase in γδ‐hi cells in the circulation of patients with nonradiographic axial SpA was remarkably reversed upon treatment with tumor necrosis factor inhibitors.…”

“…In view of the increased RORγt expression in the inflamed gut of patients with SpA, it was particularly interesting that therapeutic RORγt blockade was effective in all disease domains of a murine SpA model, including gut inflammation (40). Likewise, RORγt inhibition showed promising results in preclinical models of IBD (44,45).…”

“…A recent study, however, demonstrated gut-joint trafficking of intraepithelial T cells in a tumor necrosis factor-driven SpA model (39), supporting the idea that mucosal IL-17 potentially contributes to arthritis. Future work is required to formally assess this, including in IL-23-driven models, which are also characterized by a dominant γδ-T cell-driven IL-17 response (40). In addition, to further understand the potentially IL-23-(in)dependent properties of intestinal RORγt+ cells in SpA, it would also be of interest to study and compare IL-23R expression profiles and functional IL-23 responses of these gut-derived type 17 immune subsets.…”

GDF15 mediates inflammation-associated bone loss through a brain-bone axis

“…We circumvented this by engineering an Enhanced Episomal Vector (EEV) to express murine GDF15 under the control of a CAGs promotor ( Figure S2A ). Administering the EEV using hydrodynamic (HDD) tail vein injection results in constitutive, high levels of protein expression 26 . As a control, we used the same plasmid without the GDF15 insert (control EEV).…”