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Conversion of Th17 into exTh17 sustains rheumatoid-like IL-17-independent inflammatory arthritis [Xenium]

ABSTRACT: T helper 17 (Th17) cells are found in peripheral blood and synovial fluid of rheumatoid arthritis (RA) patients, however IL-17-targeted interventions have shown limited efficacy in established RA. While it is known that inflammation can induce Th17 transdifferentiation into Th1- or Tr1-like IL-17-negative exTh17 cells, the role of exTh17 in arthritis is not known. Here, we explore the premise that exTh17 cells promote joint inflammation in autoimmune arthritis. To assess the potential immunophenotypic dynamics and role of exTh17 in inflammatory arthritis, we performed Th17 lineage tracing studies in the SKG mouse model of RA. We show that in arthritic mice, synovial Th17 transdifferentiate into IFNγ- and IL-10- exTh17 which become the most prominent CD4+ population in chronic arthritis. SKG exTh17 cells are more arthritogenic than Th17, and able to sustain synovial inflammation that is IL-17-independent but enriched with IL-6 and TNF, two RA-promoting cytokines. Synovial exTh17 present a unique gene signature, including upregulation of CD44 and S1PR4. This gene signature has correlates in the profile of CD4+ T cells found in human RA synovium. We further demonstrate that crosstalk between Th17 and fibroblast-like synoviocytes via S1P signaling promote Th17-exTh17 conversion. Additionally, CD44 is necessary for the arthritogenic effect of exTh17. Our study suggests that the fibroblast-like synoviocyte expansion, which occurs during RA progression, can drive progressive conversion of Th17 into exTh17 which sustains inflammation with features of human established RA. The results offer new insights that could be potentially useful for future precision therapy approaches to RA.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293970 | GEO | 2026/03/25

REPOSITORIES: GEO

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Project description:The pathogenesis of rheumatoid arthritis (RA) is complicated and involves both innate and adaptive immunity [5]. The innate immunity such as macrophages or fibroblast-like synoviocytes (FLS) in the synovium can generate inflammatory mediators, including TNF-α, IL-1, IL-6, IL-17, IFN-γ, and chemo kines that lead to synovial inflammation, bone erosion, and cartilage damage [6-8]. The IL-17 signaling mediates the autoantibody production in collagen-induced arthritis (CIA) model [9]. However, the treatment response with an anti-IL17 monoclonal antibody in RA patients shows a high degree of heterogeneity [10]. The inhibitors of the Janus kinase (JAK) pathway are approved for RA patients [11]. These data suggest that the targeted multiple cytokines through the JAK pathway are useful for RA treatment. Disturbance of type I IFNs (IFNs-I) signaling and production drive autoimmune development [12]. The presymptomatic RA patients display an increase of IFNs-I before the onset of symptoms [13]. The RA patients also show the elevation of IFN- α in the synovial fluid and high expression of IFNs-I regulated gene in peripheral blood mononuclear cells (PBMC) [14]. However, the role of IFNs-I in arthritis and bone homeostasis has suggested the accelerating effect of arthritis and bone damage. The interferon-alpha receptor knockout mice develop arthritis severity higher than wild-type mice in the model of antigen-induced arthritis [15]. IFNs-I also affects the bone homeostasis by inhibiting osteoclastogenesis via receptor activator of nuclear factor-kappa B (RANK) pathway, and reduction of c-FOS expression [16-18]. Therefore, the goal of RA treatment with antagonizing the IFNs-I pathway has to be optimized between efficacy and potentially adverse effect. STING is a cytosolic DNA sensor that initiates the production of IFNs-I. STING functions have been reported as both pro-inflammatory signaling and negative regulator against inflammation [19-21]. The mutation in exon 5 of the STING gene results in gain function leading to initiate inflammation and cause the Sting associated vasculopathy with onset in infancy (SAVI) [22]. Loss of STING function rescues DNaseII-deficient mice from lethality and polyarthritis [23]. However, Sting-deficient lupus mice (MRL/Lpr mice) show higher and earlier mortality than Sting-sufficient MRL/Lpr mice [24]. The pathology also shows lymphoid hypertrophy with a higher amount of macrophages and granulocytes infiltration, autoantibodies, and cytokine [24]. The objective of this study was to identify the role of STING in the pathogenesis of rheumatoid arthritis using collagen-induced arthritis (CIA) model as a representative model of the human RA.

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Conversion of Th17 into exTh17 sustains rheumatoid-like IL-17-independent inflammatory arthritis [Xenium]

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