An evidence that SARS-Cov-2/COVID-19 spike protein (SP) damages hematopoietic stem/progenitor cells in the mechanism of pyroptosis in Nlrp3 inflammasome-dependent manner.
An evidence that SARS-Cov-2/COVID-19 spike protein (SP) damages hematopoietic stem/progenitor cells in the mechanism of pyroptosis in Nlrp3 inflammasome-dependent manner.
复制标题
SARS-COV-2/COVID-19-SPIKE蛋白（SP）以NLRP3炎症体依赖性方式损害了造血干/祖细胞的证据。
DOI：
10.1038/s41375-021-01332-z
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发表时间：
2021-10
期刊：
影响因子：
11.4
通讯作者：
Ratajczak MZ
中科院分区：
文献类型：
--
作者：
Kucia M;Ratajczak J;Bujko K;Adamiak M;Ciechanowicz A;Chumak V;Brzezniakiewicz-Janus K;Ratajczak MZ
越来越多的证据表明，造血干细胞/祖细胞（HSPCs）和内皮祖细胞（EPCs）在严重的SARS-Cov-2/COVID-19感染期间受损[1,2]。据报道，感染COVID-19的患者常出现贫血、淋巴细胞减少和血小板减少[1-3]。这种病毒对人造血和内皮的负面影响已在感染患者中得到报道，并在细胞暴露于SARS-Cov-2/COVID-19刺突蛋白（SP）后在体外得到证实[1,3,4]。众所周知，病毒可以进入细胞，在产生性感染的情况下，直接导致细胞不可逆转的损害。另一方面，病毒SP与细胞表面表达的一些受体的相互作用也可能导致它们的损伤[1-3]。我们提出SP与靶细胞表面受体的相互作用可诱导细胞内Nlrp3炎性体的过度活化，从而导致细胞热亡[5]。众所周知，焦亡的特征是以caspase-1依赖的方式在细胞膜上产生n -气凝胶蛋白孔，导致细胞质成分释放到细胞外空间并最终细胞裂解[6]。据报道，SARS-CoV-2/COVID-19利用SP与血管紧张素转换酶2 （ACE2）受体结合并随后内化后进入人细胞。此外，SP的跨膜蛋白酶2 （TMPRSS2）裂解可能增加病毒进入[7]。这促进了它与ACE2的相互作用以及随后的病毒和细胞膜的融合。另一个被认为参与病毒进入的受体是toll样受体-4 (TLR4)[8]。因此，该病毒使用在血管紧张素II转化为血管紧张素（1-7）（Ang[1-7]）中发挥生理作用的细胞表面受体，因为它属于模式识别细胞表面受体家族的ACE2和TLR4，负责炎症细胞因子的产生和固有免疫反应的激活。研究表明，ACE2和TLR4在HSPCs和EPCs上均有高表达[3,4]。除了这两种受体外，SARS-CoV-2/COVID-19还可能与细胞外基质金属蛋白酶诱导剂基底蛋白相互作用，即分化簇147 (CD147)[9]，以及最近提出的c型凝集素受体和Tweety家族成员2[10]。在我们最近关于白血病的观点论文中，我们提出，感染对干细胞室室的不良影响是由于Nlrp3炎性小体[5]的不受控制的过度激活造成的。为了支持这一点，我们注意到将人ucb纯化的CD34+ lin-CD45 + hsc暴露于重组SP中16小时可导致Nlrp3炎性体[4]mRNA表达上调。通过ELISA检测，我们还检测到暴露于SP[4]的细胞的条件培养基（CM）中IL-1β水平升高。以caspase-1依赖性的方式从细胞中释放IL-1β是Nlrp3炎性体激活的重要指标。这封致编辑的信报道了人类CD34+ HSPCs细胞和人类CD34+ CD133+ CD31+ CD144+ EPCs细胞在暴露于SP后激活Nlrp3炎性体，这是通过使用功能敏感的生物发光法测量caspase-1的细胞质活性来证明的。图1a显示caspase-1在HSPCs中响应SP而被激活，图1b显示同样的现象发生在EPCs中。此外，SP与人重组ACE2蛋白（rhACE2）预孵育后，这种激活被抑制。有趣的是，与…相比，EPCs中Nlrp3炎性体的激活更高。
Mounting evidence accumulates that hematopoietic stem/progenitor cells (HSPCs) and endothelial progenitor cells (EPCs) are damaged during severe SARS-Cov-2/COVID-19 infection [1, 2]. It has been reported that patient infected with COVID-19 are frequently presented with anemia, lymphopenia, and thrombocytopenia [1–3]. This negative effect of the virus on human hematopoiesis and endothelium has been reported in infected patients and demonstrated in vitro after exposure of cells to SARS-Cov-2/COVID-19 spike protein (SP)[1, 3, 4]. It is known that virus may enter cells and, directly in case of productive infection, lead to their irreversible damage. On the other hand, the interaction of viral SP with some of the receptors expressed on the cell surface may lead to their damage as well [1–3]. We have proposed that interaction of SP with the target cell surface receptors induces intracellular hyperactivation of Nlrp3 inflammasome which may lead to cell death by pyroptosis [5]. It is known that pyroptosis is characterized by the creation in a caspase-1 dependent manner of N-gasdermin pores in the cell membrane, which leads to the release of cytosol components to extracellular space and final cell lysis [6]. As reported, SARS-CoV-2/COVID-19 enters human cells after binding to the angiotensin-converting enzyme 2 (ACE2) receptor utilizing SP for attachment and subsequent internalization. Moreover, transmembrane protease 2 (TMPRSS2) cleavage of SP may augment viral entry [7]. This facilitates its interaction with ACE2 and the subsequent fusion of viral and cellular membranes. The other receptor postulated to be involved in virus entry is toll-like receptor-4 (TLR4)[8]. Thus, this virus is using cell surface receptors that play a physiological role in the conversion of angiotensin II to angiotensin (1–7)(Ang [1–7]) as it is a case of ACE2 and TLR4 which belongs to pattern recognition cell surface receptor family and is responsible for inflammatory cytokine production and activation of the innate immunity responses. As demonstrated, both ACE2 and TLR4 are highly expressed on HSPCs and EPCs [3, 4]. In addition to these two receptors, SARS-CoV-2/COVID-19 may also interact with the extracellular matrix metalloproteinase inducer basigin, known as cluster of differentiation 147 (CD147)[9] as well as recently proposed with C-type lectin receptor and Tweety family member 2 [10]. In our recent perspective paper in Leukemia, we proposed that the adverse effects of infection on stem cell compartments result from the uncontrolled hyperactivation of the Nlrp3 inflammasome [5]. To support this, we noticed that exposure of human UCB-purified CD34+ lin–CD45+ HSCs to recombinant SP for 16 h lead to upregulation of mRNA expression for Nlrp3 inflammasome [4]. As determined by ELISA, we also detected elevated levels of IL-1β in the conditioned media (CM) from cells exposed to SP [4]. Release from cells of IL-1β in a caspase-1-dependent manner is an important indicator of Nlrp3 inflammasome activation. This Letter to Editor reports that human CD34+ cells enriched for HSPCs and human CD34+ CD133+ CD31+ CD144+ cells enriched for EPCs activate Nlrp3 inflammasome after exposure to SP as evidenced by measuring the cytosolic activity of caspase-1 by employing functional sensitive bioluminescent glow assay. Fig. 1 A shows that caspase-1 becomes activated in HSPCs in response to SP, and Fig. 1 B shows that the same phenomenon occurs in EPCs. Moreover, this activation has been inhibited after preincubation of SP with human recombinant ACE2 protein (rhACE2). Interestingly, activation of Nlrp3 inflammasome was higher in EPCs as compared to …
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