IL-33 in COVID-19: friend or foe?
IL-33 in COVID-19: friend or foe?
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新冠肺炎里的IL-33：朋友还是敌人？
DOI：
10.1038/s41423-021-00685-w
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发表时间：
2021-06
影响因子：
24.1
通讯作者：
Sun J
中科院分区：
文献类型：
--
作者：
Liang Y;Ge Y;Sun J
由高度传染性和致病性严重急性呼吸系统综合征冠状病毒2 （sars - cov -2）引起的COVID-19大流行，截至2021年3月，已导致全球270多万人死亡。尽管人们正在努力揭示COVID-19的免疫病理学，但在某些个体中引发高炎症反应并导致严重临床结果的关键因素和过程仍不清楚。损伤相关分子模式（DAMP）分子IL-33属于IL-1家族，已被认为是指示细胞损伤或感染的警报蛋白。全长IL-33需要蛋白酶裂解才能产生成熟的生物活性形式，它可以与ST2受体（也称为IL-1RL1）结合，从而激活各种先天和适应性免疫细胞中的NF-κB通路。IL-33在上皮细胞和内皮细胞中相对较高的丰度解释了其在呼吸系统疾病中的促炎作用。最近的观察显示，老年COVID-19患者血清IL-33上调，并与不良结局相关。2,3严重感染时IL-33水平升高可能是由于气道上皮和活化的免疫细胞之间的强烈相互作用引起的上皮损伤。sars - cov -2衍生的木瓜蛋白酶（PLpro）是上皮细胞中IL-33的强大诱导性因子，4也可能触发上皮来源的IL-33，在肺部引发炎症反应。为检测SARS-CoV-2感染是否诱导上皮细胞IL-33的表达，我们用SARS-CoV-2（病毒株：BetaCoV/JS02/ human /2019，由江苏省疾病预防控制中心分离）体外感染两株人上皮细胞Fadu和LS513。我们的研究结果显示，在感染后72小时，两种细胞系中IL-33转录水平显著增加（图1a）。因此，我们首次提供了SARS-CoV-2感染促进人上皮细胞中IL-33表达的证据。临床，对COVID-19患者支气管肺泡灌洗液的转录组学分析显示IL-33的强烈上调，5表明感染后IL-33在肺募集细胞（如巨噬细胞）中被诱导。此外，最近的一篇预印本报道称，SARS-CoV-2刺突肽混合物可以诱导血清阳性个体的pbmc培养上清中分泌IL-33, 6表明免疫细胞也可能是COVID-19中IL-33的来源。然而，IL-33是由活化的免疫细胞分泌还是由于细胞死亡而直接释放尚不清楚。成熟的IL-33与ST2和IL-1RAcP组成的受体复合物结合后，通过激活嗜酸性粒细胞、肥大细胞、M2巨噬细胞、T辅助2细胞和2组先天淋巴样细胞（ILC2s）来增强2型免疫。1与sars - cov相比，sars - cov -2倾向于低水平表达1型细胞因子（IL-12p70和IL-15），高水平表达Th2/9型细胞因子（IL-4、IL-9、IL-10、IL-13和TGF-β）的细胞因子风暴。7 2型细胞因子水平升高与COVID-19患者ILC2s数量增加相关3并可能促进致病性γδ T细胞（IFN-γlow GM-CSFhigh）的分化。因此，sars - cov -2感染后肺中IL-33的升高可能是2型免疫细胞因子的驱动力，并解释了呼吸免疫失调。此外，il -33依赖的肺驻留ILC2s可以通过抑制IFN-γ的产生和细胞毒性功能来调节NK细胞的先天免疫，8导致NK细胞对SARS的反应受损。
The COVID-19 pandemic, caused by the highly transmissible and pathogenic severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2), has led to more than 2.7 million deaths worldwide as of March 2021. Although considerable efforts are underway to reveal the immunopathology of COVID-19, the key factors and processes that initiate hyperinflammatory responses and cause severe clinical outcomes in certain individuals remain unclear. The damageassociated molecular pattern (DAMP) molecule IL-33 belongs to the IL-1 family and has been recognized as an alarmin that indicates cellular damage or infection. Full-length IL-33 requires cleavage by proteases to generate its mature bioactive form, which can bind to the ST2 receptor (also known as IL-1RL1), leading to activation of the NF-κB pathway in various innate and adaptive immune cells. The relatively high abundance of IL-33 in epithelial and endothelial cells accounts for its proinflammatory role in respiratory diseases. 1 Recent observations have revealed that serum IL-33 is upregulated in elderly patients with COVID-19 and associated with adverse outcomes. 2, 3 The increased IL-33 levels in severe infection could result from epithelial damage caused by strong interactions between the airway epithelium and activated immune cells. SARS-CoV-2-derived papain-like protease (PLpro), a powerful inducer of IL-33 in epithelial cells, 4 may also trigger epithelium-derived IL-33 to initiate inflammatory responses in the lungs. To test whether SARS-CoV-2 infection induces IL-33 expression in epithelial cells, we infected two human epithelial cell lines, Fadu and LS513, with SARS-CoV-2 (viral strain: BetaCoV/JS02/Human/2019, isolated by Jiangsu Provincial Center for Disease Control and Prevention, China) in vitro. Our results demonstrated significant increases in IL-33 transcript levels in both cell lines at 72 h postinfection (Fig. 1 A). Therefore, we provide evidence for the first time that SARS-CoV-2 infection promotes IL-33 expression in human epithelial cells. Clinically, transcriptomic analysis of bronchoalveolar lavage fluid from COVID-19 patients demonstrated strong upregulation of IL-33, 5 indicating the induction of IL-33 in pulmonary recruited cells (eg, macrophages) after infection. Moreover, a recent preprint reported that a SARS-CoV-2 spike peptide mixture could induce IL-33 secretion in the culture supernatant of PBMCs from seropositive individuals, 6 suggesting that immune cells may also be a source of IL-33 in COVID-19. However, it is not clear whether IL-33 is secreted by activated immune cells or is directly released due to cell death. Upon binding with a receptor complex composed of ST2 and IL-1RAcP, mature IL-33 boosts type-2 immunity via the activation of eosinophils, mast cells, M2 macrophages, T helper 2 cells and group 2 innate lymphoid cells (ILC2s). 1 Compared with severe acute respiratory syndrome coronavirus (SAR-CoV), SAR-CoV-2 favors a cytokine storm composed of low levels of type 1 cytokines (IL-12p70 and IL-15) but high expression of Th2/9 cytokines (IL-4, IL-9, IL-10, IL-13 and TGF-β). 7 Elevated type 2 cytokine levels correlated with an increased number of ILC2s in COVID-19 patients 3 and may contribute to the differentiation of pathogenic γδ T cells (IFN-γlow GM-CSFhigh). Therefore, an elevation in IL-33 in the lungs following SAR-CoV-2 infection might be the driving force of type 2 immune cytokines and account for respiratory immune dysregulation. Moreover, IL-33-dependent lung-resident ILC2s can modulate NK cell innate immunity by suppressing IFN-γ production and cytotoxic functions, 8 leading to an impaired NK cell responses against SARS …
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影响因子：
24.1
作者：
Liang, Yuejin;Yi, Panpan;Sun, Jiaren
通讯作者：
Sun, Jiaren
影响因子：
28.2
作者：
Liu, Yuwei;Du, Xuebei;Zhao, Yan
通讯作者：
Zhao, Yan
影响因子：
14.2
作者：
Lynch, Jason P.;Werder, Rhiannon B.;Phipps, Simon
通讯作者：
Phipps, Simon
影响因子：
30.5
作者：
Schuijs, Martijn J.;Png, Shaun;Halim, Timotheus Y. F.
通讯作者：
Halim, Timotheus Y. F.
影响因子：
5.8
作者：
Burke H;Freeman A;Cellura DC;Stuart BL;Brendish NJ;Poole S;Borca F;Phan HTT;Sheard N;Williams S;Spalluto CM;Staples KJ;Clark TW;Wilkinson TMA;REACT COVID investigators
通讯作者：
REACT COVID investigators