P2Y14 Receptor as a Target for Neutrophilia Attenuation in Severe COVID-19 Cases: From Hematopoietic Stem Cell Recruitment and Chemotaxis to Thrombo‐inflammation
- 11 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Stem Cell Reviews and Reports
- Vol. 17 (1), 241-252
- https://doi.org/10.1007/s12015-021-10129-7
Abstract
The global SARS-CoV-2 pandemic starting in 2019 has already reached more than 2.3 million deaths. Despite the scientific community’s efforts to investigate the COVID-19 disease, a drug for effectively treating or curing patients yet needs to be discovered. Hematopoietic stem cells (HSC) differentiating into immune cells for defense express COVID-19 entry receptors, and COVID-19 infection hinders their differentiation. The importance of purinergic signaling in HSC differentiation and innate immunity has been recognized. The metabotropic P2Y14 receptor subtype, activated by UDP-glucose, controls HSC differentiation and mobilization. Thereon, the exacerbated activation of blood immune cells amplifies the inflammatory state observed in COVID-19 patients, specially through the continuous release of reactive oxygen species and extracellular neutrophil traps (NETs). Further, the P2Y14 subtype, robustly inhibits the infiltration of neutrophils into various epithelial tissues, including lungs and kidneys. Here we discuss findings suggesting that antagonism of the P2Y14 receptor could prevent the progression of COVID-19-induced systemic inflammation, which often leads to severe illness and death cases. Considering the modulation of neutrophil recruitment of extreme relevance for respiratory distress and lung failure prevention, we propose that P2Y14 receptor inhibition by its selective antagonist PPTN could limit neutrophil recruitment and NETosis, hence limiting excessive formation of oxygen reactive species and proteolytic activation of the kallikrein-kinin system and subsequent bradykinin storm in the alveolar septa of COVID-19 patients. Graphical AbstractKeywords
Funding Information
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (380405/2020-2)
- Fundação de Amparo à Pesquisa do Estado de São Paulo (2015/13345-1-PD)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq Rede COVID-Rio)
- National Institutes of Health (2R01 DK074720)
- Fundação de Amparo à Pesquisa do Estado de São Paulo (2018/07366-4)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (306392/2017-8)
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