Paradoxical Activation of Entheseal Myeloid Cells by JAK1 and TYK2 Inhibitors via IL10 Antagonism

IF 11.4 1区医学 Q1 RHEUMATOLOGY

Arthritis & Rheumatology Pub Date : 2025-05-05 DOI:10.1002/art.43210

Sami Giryes, Chi Wong, Charlie Bridgewood, Mark Harland, Ala Altaie, Nicole McDermott, Kerem Abacar, Abhay Rao, Almas Khan, Tristan McMillan, Peter Loughenbery, Robert Dunsmuir, Vishal Borse, Tom Macleod, Dennis McGonagle

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引用次数: 0

Abstract

BackgroundJAK 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's 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 TLR agonists, including TLR4 and IL‐1 family proteins and entheseal T cell were activated with anti‐CD3/anti‐CD28 plus 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 RNAseq and cytokine blocking or stimulation.ResultsFollowing IFNγ stimulation, JAK1 inhibition blocked STAT1 phosphorylation in entheseal cells and strongly blocked activated entheseal T cell 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 multifaceted impact of JAKi on myeloid activation with strong M1 type monocyte polarisation 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.ConclusionsThese 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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JAK1和TYK2抑制剂通过il - 10拮抗作用对尾髓细胞的矛盾激活

JAK抑制（JAKi）在血清阴性脊柱关节病（SpA）谱系障碍中有效，但TYK2抑制在SpA谱系溃疡性结肠炎中无效，托法替尼在克罗恩病中显示出最小的益处，这突出了JAK‐STAT信号在不同炎症过程中的复杂作用。在这项研究中，我们研究了JAKi是否可能矛盾地激活内源性先天免疫，并旨在确定参与这一过程的关键调节细胞因子。方法用TLR受体激动剂（包括TLR4和IL‐1家族蛋白）激活脊髓后端组织，用抗CD3/抗CD28 + IL‐23/IL‐1β激活脊髓后端T细胞。JAKi通过upadacitinib （JAK1/JAK2）、deucravacitinib （TYK2）和ritlecitinib （JAK3）的抑制作用，通过多种细胞因子测定、细胞内流量和体积RNAseq以及细胞因子阻断或刺激来评估。结果在IFNγ刺激后，JAK1抑制抑制了内皮细胞中STAT1的磷酸化，并强烈阻断了激活的内皮T细胞TNFα、IL - 17A和IL - 17F的产生。在内皮髓细胞中，TLR4和其他佐剂介导的细胞因子（包括IL - 23）的产生量增加了10倍，而TLR4和其他佐剂介导的细胞因子的产生量则明显相反。p & lt;0.001)或tnf - α(~10倍增加；p & lt;0.0001)。这种髓细胞效应是由upadacitinib和deucravacitinib诱导的，而不是利来替尼，提示IL‐10R JAK1/TYK2信号通路。Bulk RNAseq显示JAKi对髓细胞活化的多方面影响，在TLR4刺激和流式细胞术证实的JAK1抑制下，具有强M1型单核细胞极化。直接IL - 10抑制重现炎症细胞因子升高，IL - 10R激动剂在很大程度上（但不是完全）挽救了这种表型。结论：这些发现有助于解释TYK2阻断在不依赖IL - 10的SpA谱相关关节炎中的紧急疗效，但也说明了为什么这些策略可能不是SpA谱障碍相关肠道炎症的灵丹妙药

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Arthritis & Rheumatology RHEUMATOLOGY-

CiteScore

20.90

自引率

3.00%

发文量

371

期刊介绍： Arthritis & Rheumatology is the official journal of the American College of Rheumatology and focuses on the natural history, pathophysiology, treatment, and outcome of rheumatic diseases. It is a peer-reviewed publication that aims to provide the highest quality basic and clinical research in this field. The journal covers a wide range of investigative areas and also includes review articles, editorials, and educational material for researchers and clinicians. Being recognized as a leading research journal in rheumatology, Arthritis & Rheumatology serves the global community of rheumatology investigators and clinicians.