Division of Molecular Microbiology, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, United States.
UCF Health, College of Medicine, University of Central Florida, Orlando, FL, United States.
Front Immunol. 2021 May 6;12:641295. doi: 10.3389/fimmu.2021.641295. eCollection 2021.
Although millions of patients with underlining conditions are treated primarily with anti-TNF-α agents, little is known about the safety of this standard therapy during the coronavirus disease-2019 (COVID-19) pandemic. In this study, we investigated the effect of anti-TNF-α monoclonal antibodies on the cellular entry mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and increasing the risk of COVID-19 development. We focused on the expression of angiotensin-converting enzyme II (ACE2), type II transmembrane serine proteases (TMPRSS2)/TNF-α converting enzyme (TACE) ratio. We also investigated the involvement of Notch-1 signaling and its downstream influence on IL-6, myeloid cell leukemia sequence-1(MCL-1) in the anti-TNF-α mode of action and increased the susceptibility to (MAP) infection. Surprisingly, anti-TNF-α downregulated ACE2 expression by 0.46-fold and increased TMPRSS2/TACE ratio by 44% in THP-1 macrophages. Treatment of macrophages with rIL-6 also downregulated ACE2 and increased TMPRSS2/TACE ratio by 54%. Interestingly, anti-TNF-α treatment upregulated Notch-1, IL-6, and MCL-1 by 1.3, 1.2, and 1.9-fold, respectively, and increased viability and burden of MAP infection in macrophages. Blocking Notch signaling doubled ACE2 expression, decreased TMPRSS2/TACE ratio by 38%, and reduced MAP viability by 56%. In a small group of patients, ACE2 level was significantly lower in the plasma from rheumatoid arthritis (RA) patients on anti-TNF-α treatment compared to healthy control. The data in this critical study demonstrated that through Notch-1/IL-6 signaling, anti-TNF-α agents decreased ACE2 expression and shedding through TMPRSS2/TACE modulation and increased the susceptibility to infection. Overall, this study warns against anti-TNF-α therapy in some patients with underlining inflammatory conditions during the COVID-19 pandemic. The findings should impact current guidelines regarding treatment decisions of patients on anti-TNF-α during the COVID-19 pandemic.
尽管数以百万计的基础疾病患者主要接受抗 TNF-α 药物治疗，但在 2019 年冠状病毒病（COVID-19）大流行期间，人们对这种标准疗法的安全性知之甚少。在这项研究中，我们研究了抗 TNF-α 单克隆抗体对严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）细胞进入机制的影响，以及增加 COVID-19 发展的风险。我们专注于血管紧张素转换酶 II（ACE2）的表达，Ⅱ型跨膜丝氨酸蛋白酶（TMPRSS2）/TNF-α 转化酶（TACE）比值。我们还研究了 Notch-1 信号通路的参与及其对白细胞介素 6（IL-6）、髓样细胞白血病序列 1（MCL-1）的下游影响，这些影响与抗 TNF-α作用模式和增加对 SARS-CoV-2 的易感性有关。令人惊讶的是，抗 TNF-α 使 THP-1 巨噬细胞中的 ACE2 表达下调了 0.46 倍，并使 TMPRSS2/TACE 比值增加了 44%。用 rIL-6 处理巨噬细胞也使 ACE2 下调，TMPRSS2/TACE 比值增加 54%。有趣的是，抗 TNF-α 处理使 Notch-1、IL-6 和 MCL-1 分别上调 1.3、1.2 和 1.9 倍，并增加了巨噬细胞中 MAP 感染的活力和负担。阻断 Notch 信号使 ACE2 表达增加一倍，TMPRSS2/TACE 比值降低 38%，MAP 活力降低 56%。在一小部分患者中，与健康对照组相比，接受抗 TNF-α治疗的类风湿关节炎（RA）患者血浆中的 ACE2 水平显著降低。这项关键研究的数据表明，通过 Notch-1/IL-6 信号通路，抗 TNF-α 药物通过 TMPRSS2/TACE 调节降低 ACE2 的表达和脱落，并增加感染的易感性。总的来说，这项研究警告在 COVID-19 大流行期间，一些基础炎症性疾病患者慎用抗 TNF-α 治疗。这些发现应该影响目前关于 COVID-19 大流行期间接受抗 TNF-α 治疗患者治疗决策的指南。
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