Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, 02115, USA.
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.
Genome Med. 2021 Apr 20;13(1):64. doi: 10.1186/s13073-021-00881-3.
Immunosuppressive and anti-cytokine treatment may have a protective effect for patients with COVID-19. Understanding the immune cell states shared between COVID-19 and other inflammatory diseases with established therapies may help nominate immunomodulatory therapies.
To identify cellular phenotypes that may be shared across tissues affected by disparate inflammatory diseases, we developed a meta-analysis and integration pipeline that models and removes the effects of technology, tissue of origin, and donor that confound cell-type identification. Using this approach, we integrated > 300,000 single-cell transcriptomic profiles from COVID-19-affected lungs and tissues from healthy subjects and patients with five inflammatory diseases: rheumatoid arthritis (RA), Crohn's disease (CD), ulcerative colitis (UC), systemic lupus erythematosus (SLE), and interstitial lung disease. We tested the association of shared immune states with severe/inflamed status compared to healthy control using mixed-effects modeling. To define environmental factors within these tissues that shape shared macrophage phenotypes, we stimulated human blood-derived macrophages with defined combinations of inflammatory factors, emphasizing in particular antiviral interferons IFN-beta (IFN-β) and IFN-gamma (IFN-γ), and pro-inflammatory cytokines such as TNF.
We built an immune cell reference consisting of > 300,000 single-cell profiles from 125 healthy or disease-affected donors from COVID-19 and five inflammatory diseases. We observed a CXCL10+ CCL2+ inflammatory macrophage state that is shared and strikingly abundant in severe COVID-19 bronchoalveolar lavage samples, inflamed RA synovium, inflamed CD ileum, and UC colon. These cells exhibited a distinct arrangement of pro-inflammatory and interferon response genes, including elevated levels of CXCL10, CXCL9, CCL2, CCL3, GBP1, STAT1, and IL1B. Further, we found this macrophage phenotype is induced upon co-stimulation by IFN-γ and TNF-α.
Our integrative analysis identified immune cell states shared across inflamed tissues affected by inflammatory diseases and COVID-19. Our study supports a key role for IFN-γ together with TNF-α in driving an abundant inflammatory macrophage phenotype in severe COVID-19-affected lungs, as well as inflamed RA synovium, CD ileum, and UC colon, which may be targeted by existing immunomodulatory therapies.
免疫抑制和抗细胞因子治疗可能对 COVID-19 患者具有保护作用。了解 COVID-19 与其他具有既定治疗方法的炎症性疾病之间共同的免疫细胞状态，可能有助于提名免疫调节治疗。
为了确定可能在不同炎症性疾病影响的组织中共享的细胞表型，我们开发了一种元分析和集成管道，该管道可模拟和消除混淆细胞类型识别的技术、组织起源和供体的影响。使用这种方法，我们整合了 >300,000 个来自 COVID-19 受影响的肺和来自健康受试者以及五种炎症性疾病患者的组织的单细胞转录组谱：类风湿关节炎 (RA)、克罗恩病 (CD)、溃疡性结肠炎 (UC)、系统性红斑狼疮 (SLE) 和间质性肺病。我们使用混合效应模型测试了与健康对照组相比，共享免疫状态与严重/炎症状态的相关性。为了定义这些组织中塑造共享巨噬细胞表型的环境因素，我们用定义的炎症因子组合刺激人血液衍生的巨噬细胞，特别强调抗病毒干扰素 IFN-β (IFN-β) 和 IFN-γ (IFN-γ)，以及促炎细胞因子，如 TNF。
我们构建了一个免疫细胞参考，由来自 COVID-19 和五种炎症性疾病的 125 名健康或疾病受影响的供体的 >300,000 个单细胞图谱组成。我们观察到一种 CXCL10+CCL2+ 炎症性巨噬细胞状态，在严重 COVID-19 支气管肺泡灌洗液样本、炎症性 RA 滑膜、炎症性 CD 回肠和 UC 结肠中均有共享且非常丰富。这些细胞表现出促炎和干扰素反应基因的独特排列，包括 CXCL10、CXCL9、CCL2、CCL3、GBP1、STAT1 和 IL1B 的水平升高。此外，我们发现这种巨噬细胞表型在 IFN-γ 和 TNF-α 共同刺激时被诱导。
我们的综合分析确定了炎症性疾病和 COVID-19 影响的炎症组织中共同的免疫细胞状态。我们的研究支持 IFN-γ 与 TNF-α 一起在严重 COVID-19 受影响的肺部、炎症性 RA 滑膜、CD 回肠和 UC 结肠中驱动丰富的炎症性巨噬细胞表型中发挥关键作用，这可能是现有免疫调节治疗的靶点。
