严重急性呼吸综合征冠状病毒2感染引发银屑病关节炎发作，且通过JAK拮抗作用对驻跗骨浆细胞样树突状细胞1型干扰素的抑制为脊柱关节炎发病机制提供了新见解。
SARS-CoV-2 Infection Induces Psoriatic Arthritis Flares and Enthesis Resident Plasmacytoid Dendritic Cell Type-1 Interferon Inhibition by JAK Antagonism Offer Novel Spondyloarthritis Pathogenesis Insights.
作者信息
Zhou Qiao, Vadakekolathu Jayakumar, Watad Abdulla, Sharif Kassem, Russell Tobias, Rowe Hannah, Khan Almas, Millner Peter A, Loughenbury Peter, Rao Abhay, Dunsmuir Robert, Timothy Jake, Damiani Giovanni, Pigatto Paolo D M, Malagoli Piergiorgio, Banfi Giuseppe, El-Sherbiny Yasser M, Bridgewood Charlie, McGonagle Dennis
机构信息
Department of Rheumatology and Immunology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China.
出版信息
Front Immunol. 2021 Apr 15;12:635018. doi: 10.3389/fimmu.2021.635018. eCollection 2021.
OBJECTIVE
Bacterial and viral infectious triggers are linked to spondyloarthritis (SpA) including psoriatic arthritis (PsA) development, likely dendritic cell activation. We investigated spinal entheseal plasmacytoid dendritic cells (pDCs) toll-like receptor (TLR)-7 and 9 activation and therapeutic modulation, including JAK inhibition. We also investigated if COVID-19 infection, a potent TLR-7 stimulator triggered PsA flares.
METHODS
Normal entheseal pDCs were characterized and stimulated with imiquimod and CpG oligodeoxynucleotides (ODN) to evaluate TNF and IFNα production. NanoString gene expression assay of total pDCs RNA was performed pre- and post- ODN stimulation. Pharmacological inhibition of induced IFNα protein was performed with Tofacitinib and PDE4 inhibition. The impact of SARS-CoV2 viral infection on PsA flares was evaluated.
RESULTS
CD45+HLA-DR+CD123+CD303+CD11c- entheseal pDCs were more numerous than blood pDCs (1.9 ± 0.8% vs 0.2 ± 0.07% of CD45+ cells, p=0.008) and showed inducible IFNα and TNF protein following ODN/imiquimod stimulation and were the sole entheseal IFNα producers. NanoString data identified 11 significantly upregulated differentially expressed genes (DEGs) including TNF in stimulated pDCs. Canonical pathway analysis revealed activation of dendritic cell maturation, NF-κB signaling, toll-like receptor signaling and JAK/STAT signaling pathways following ODN stimulation. Both tofacitinib and PDE4i strongly attenuated ODN induced IFNα. DAPSA scores elevations occurred in 18 PsA cases with SARS-CoV2 infection (9.7 ± 4 pre-infection and 35.3 ± 7.5 during infection).
CONCLUSION
Entheseal pDCs link microbes to TNF/IFNα production. SARS-CoV-2 infection is associated with PsA Flares and JAK inhibition suppressed activated entheseal plasmacytoid dendritic Type-1 interferon responses as pointers towards a novel mechanism of PsA and SpA-related arthropathy.
目的
细菌和病毒感染触发因素与包括银屑病关节炎（PsA）在内的脊柱关节炎（SpA）的发病有关，可能与树突状细胞活化有关。我们研究了脊柱附着点浆细胞样树突状细胞（pDCs）的Toll样受体（TLR）-7和9的活化及治疗性调节，包括JAK抑制。我们还研究了作为一种有效的TLR-7刺激剂的新型冠状病毒肺炎（COVID-19）感染是否会引发PsA病情加重。
方法
对正常附着点pDCs进行表征，并用咪喹莫特和CpG寡脱氧核苷酸（ODN）刺激，以评估肿瘤坏死因子（TNF）和α干扰素（IFNα）的产生。在ODN刺激前后对总pDCs RNA进行纳米串基因表达分析。用托法替布和磷酸二酯酶4（PDE4）抑制对诱导的IFNα蛋白进行药理学抑制。评估严重急性呼吸综合征冠状病毒2（SARS-CoV2）病毒感染对PsA病情加重的影响。
结果
CD45+HLA-DR+CD123+CD303+CD11c-附着点pDCs比血液pDCs数量更多（分别占CD45+细胞的1.9±0.8%和0.2±0.07%，p=0.008），并且在ODN/咪喹莫特刺激后显示出可诱导的IFNα和TNF蛋白，且是附着点唯一的IFNα产生细胞。纳米串数据确定了11个显著上调的差异表达基因（DEG），包括刺激后pDCs中的TNF。经典通路分析显示ODN刺激后树突状细胞成熟、核因子κB（NF-κB）信号传导、Toll样受体信号传导和JAK/信号转导和转录激活因子（STAT）信号通路的激活。托法替布和PDE4抑制剂均强烈减弱ODN诱导的IFNα。18例感染SARS-CoV2的PsA患者疾病活动评分（DAPSA）升高（感染前为9.7±4，感染期间为35.3±7.5）。
结论
附着点pDCs将微生物与TNF/IFNα的产生联系起来。SARS-CoV-2感染与PsA病情加重相关，JAK抑制可抑制活化的附着点浆细胞样树突状细胞I型干扰素反应，这为PsA和SpA相关关节病的新机制提供了线索。
Zotero 插件