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Article

Endothelial Cell Activation by SARS-CoV-2 Spike S1 Protein: A Crosstalk between Endothelium and Innate Immune Cells

Laboratory of General Pathology, Department of Medicine and Surgery, University of Parma, 43125 Parma, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Pasquale Ambrosino
Biomedicines 2021, 9(9), 1220; https://doi.org/10.3390/biomedicines9091220
Received: 20 July 2021 / Revised: 30 August 2021 / Accepted: 11 September 2021 / Published: 14 September 2021
Background. Emerging evidences suggest that in severe COVID-19, multi-organ failure is associated with a hyperinflammatory state (the so-called “cytokine storm”) in combination with the development of a prothrombotic state. The central role of endothelial dysfunction in the pathogenesis of the disease is to date accepted, but the precise mechanisms underlying the associated coagulopathy remain unclear. Whether the alterations in vascular homeostasis directly depend upon the SARS-CoV-2 infection of endothelial cells or, rather, occur secondarily to the activation of the inflammatory response is still a matter of debate. Here, we address the effect of the SARS-CoV-2 spike S1 protein on the activation of human lung microvascular endothelial cells (HLMVEC). In particular, the existence of an endothelium-macrophage crosstalk in the response to the spike protein has been explored. Methods and Results. The effect of the spike protein is addressed in human lung microvascular endothelial cells (HLMVEC), either directly or after incubation with a conditioned medium (CM) of human monocyte-derived macrophages (MDM) previously activated by the spike S1 protein (CM-MDM). Both MDM and HLMVEC are activated in response to the S1 protein, with an increased expression of pro-inflammatory mediators. However, when HLMVEC are exposed to CM-MDM, an enhanced cell activation occurs in terms of the expression of adhesion molecules, pro-coagulant markers, and chemokines. Under this experimental condition, ICAM-1 and VCAM-1, the chemokines CXCL8/IL-8, CCL2/MCP1, and CXCL10/IP-10 as well as the protein tissue factor (TF) are markedly induced. Instead, a decrease of thrombomodulin (THBD) is observed. Conclusion. Our data suggest that pro-inflammatory mediators released by spike-activated macrophages amplify the activation of endothelial cells, likely contributing to the impairment of vascular integrity and to the development of a pro-coagulative endothelium. View Full-Text
Keywords: COVID-19; spike S1 protein; endothelial activation; macrophages; cytokines COVID-19; spike S1 protein; endothelial activation; macrophages; cytokines
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MDPI and ACS Style

Rotoli, B.M.; Barilli, A.; Visigalli, R.; Ferrari, F.; Dall’Asta, V. Endothelial Cell Activation by SARS-CoV-2 Spike S1 Protein: A Crosstalk between Endothelium and Innate Immune Cells. Biomedicines 2021, 9, 1220. https://doi.org/10.3390/biomedicines9091220

AMA Style

Rotoli BM, Barilli A, Visigalli R, Ferrari F, Dall’Asta V. Endothelial Cell Activation by SARS-CoV-2 Spike S1 Protein: A Crosstalk between Endothelium and Innate Immune Cells. Biomedicines. 2021; 9(9):1220. https://doi.org/10.3390/biomedicines9091220

Chicago/Turabian Style

Rotoli, Bianca M., Amelia Barilli, Rossana Visigalli, Francesca Ferrari, and Valeria Dall’Asta. 2021. "Endothelial Cell Activation by SARS-CoV-2 Spike S1 Protein: A Crosstalk between Endothelium and Innate Immune Cells" Biomedicines 9, no. 9: 1220. https://doi.org/10.3390/biomedicines9091220

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