ArticleArthritis & rheumatology (Hoboken, N.J.)2025
Paradoxical Activation of Entheseal Myeloid Cells by JAK1 and Tyk2 Inhibitors via Interleukin-10 Antagonism.
Article in Arthritis & rheumatology (Hoboken, N.J.), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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3 citing papers in PubMed.
- Programmed cell death-related transcriptomic features are associated with aortic valve calcification progression: an integrated analysis of public datasets and clinical samples.Journal of thoracic disease · 2026Article
- The IL-23/IL-17 axis in Behçet's syndrome pathogenesis: from immunological perspectives to therapeutic implications.Frontiers in immunology · 2026Review
- Integrative Transcriptomic and Machine-Learning Analysis Reveals Immune-Inflammatory and Stress-Response Alterations in MRONJ.International journal of molecular sciences · 2025Article
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15 authors.
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Abstract
objectiveJAK inhibition (JAKi) is effective in seronegative spondyloarthropathy (SpA) spectrum disorders, but Tyk2 inhibition failed in SpA spectrum ulcerative colitis, and tofacitinib showed minimal benefit in Crohn disease, which highlights the complex role for JAK/STAT signaling in different inflammatory processes. In this study, we investigated whether JAKi might paradoxically activate entheseal innate immunity and aimed to identify the key regulatory cytokines involved in this process.
methodsSpinal entheseal tissue was activated with Toll-like receptor (TLR) agonists, including TLR4 and interleukin-1 (IL-1) family proteins, and entheseal T cells were activated with anti-CD3/anti-CD28 with IL-23/IL-1β. JAKi via upadacitinib (JAK1/JAK2), deucravacitinib (Tyk2), and ritlecitinib (JAK3) inhibition was evaluated using multiplex cytokine assays, intracellular flow, and bulk RNA sequencing (RNAseq) and cytokine blocking or stimulation.
resultsFollowing interferon γ stimulation, JAK1 inhibition blocked STAT1 phosphorylation in entheseal cells and strongly blocked activated entheseal T cell tumor necrosis factor α (TNFα), IL-17A, and IL-17F production. The opposite effect was evident in entheseal myeloid cell with exaggerated TLR4 and other adjuvant-mediated cytokine production including IL-23 (~10-fold increase; P < 0.001) or TNFα (~10-fold increase; P < 0.0001). This myeloid effect was induced by upadacitinib and deucravacitinib but not ritlecitinib, suggesting IL-10R JAK1/Tyk2 signaling. Bulk RNAseq showed a multifaceted impact of JAKi on myeloid activation with strong M1 type monocyte polarization under TLR4 stimulation and JAK1 inhibition confirmed by flow cytometry. Direct IL-10 inhibition recapitulated inflammatory cytokine elevations and IL-10R agonist largely, but not completely, rescued this phenotype.
conclusionThese findings help explain the emergent efficacy of Tyk2 blockade in SpA spectrum-related arthritis that is not IL-10 dependent but indicates why such strategies may not be a panacea for SpA spectrum disorder-related intestinal inflammation.
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