COVID-19 and Rheumatoid Arthritis share myeloid pathogenic and resolving pathways
COVID-19 and Rheumatoid Arthritis share myeloid pathogenic and resolving pathways
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DOI：
10.1101/2020.07.26.221572
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发表时间：
2020-07
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影响因子：
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通讯作者：
L. MacDonald;T. Otto;A. Elmesmari;B. Tolusso;D. Somma;C. McSharry;E. Gremese;I. McInnes;S. Alivernini;M. Kurowska-Stolarska
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作者：
L. MacDonald;T. Otto;A. Elmesmari;B. Tolusso;D. Somma;C. McSharry;E. Gremese;I. McInnes;S. Alivernini;M. Kurowska-Stolarska
背景我们最近描述了类风湿关节炎（RA）滑膜组织巨噬细胞簇致病和炎症的功能生物学。虽然RA不是一种病毒性呼吸道综合征，但它代表了一种促炎性尼古丁驱动的慢性关节疾病，通常伴有心血管和肺部病变。我们假设肺部功能等效的巨噬细胞簇可能会控制炎症和COVID-19肺炎的消退。方法为了深入了解COVID-19支气管肺泡灌洗（BALF）巨噬细胞簇的靶向功能，对BALF巨噬细胞单细胞转录组学（scRNA-seq）与滑膜组织（ST）巨噬细胞scRNA-seq和功能生物学进行了比较分析。在原代巨噬细胞-滑膜成纤维细胞共培养物中，用抑制剂证实了共享的BALF和ST MerTK炎症消退途径的功能。结果重症COVID-19患者中出现的不同BALF FCNpos和FCNposSPP 1 pos巨噬细胞簇与活动性RA中驱动滑膜炎的ST CD 48 highS 100 A12 pos和CD 48 posSPP 1 pos簇密切相关。它们具有共同的转录组学特征和致病机制。健康肺驻留肺泡FABP 4pos巨噬细胞共享调节转录组学谱，包括TAM（Tyro，Axl，MerTK）受体途径与滑膜组织TREM 2 pos巨噬细胞，其控制RA缓解。该途径在严重COVID-19的BALF巨噬细胞中发生了实质性改变。体外地塞米松通过巨噬细胞的MerTK功能抑制组织炎症。结论COVID-19肺炎和RA滑膜炎的发病和消退可能由相似的巨噬细胞簇和途径驱动。地塞米松的MerTK依赖性抗炎机制和维持RA缓解的TAM通路的稳态功能主张治疗性MerTK激动剂，以改善严重COVID-19的细胞因子风暴和肺炎。
Background We recently delineated the functional biology of pathogenic and inflammation resolving synovial tissue macrophage clusters in rheumatoid arthritis (RA). Whilst RA is not a viral respiratory syndrome, it represents a pro-inflammatory cytokine-driven chronic articular condition often accompanied by cardiovascular and lung pathologies. We hypothesised that functionally equivalent macrophage clusters in the lung might govern inflammation and resolution of COVID-19 pneumonitis. Methods To provide insight into the targetable functions of COVID-19 bronchoalveolar lavage (BALF) macrophage clusters, a comparative analysis of BALF macrophage single cell transcriptomics (scRNA-seq) with synovial tissue (ST) macrophage scRNA-seq and functional biology was performed. The function of shared BALF and ST MerTK inflammation-resolving pathway was confirmed with inhibitor in primary macrophage-synovial fibroblast co-cultures. Results. Distinct BALF FCNpos and FCNposSPP1pos macrophage clusters emerging in severe COVID-19 patients were closely related to ST CD48highS100A12pos and CD48posSPP1pos clusters driving synovitis in active RA. They shared transcriptomic profile and pathogenic mechanisms. Healthy lung resident alveolar FABP4pos macrophages shared a regulatory transcriptomic profile, including TAM (Tyro, Axl, MerTK) receptors pathway with synovial tissue TREM2pos macrophages that govern RA remission. This pathway was substantially altered in BALF macrophages of severe COVID-19. In vitro dexamethasone inhibited tissue inflammation via macrophages’ MerTK function. Conclusion Pathogenesis and resolution of COVID-19 pneumonitis and RA synovitis might be driven by similar macrophage clusters and pathways. The MerTK-dependent anti-inflammatory mechanisms of dexamethasone, and the homeostatic function of TAM pathways that maintain RA in remission advocate the therapeutic MerTK agonism to ameliorate the cytokine storm and pneumonitis of severe COVID-19.