P2Y14 Receptor as a Target for Neutrophilia Attenuation in Severe COVID-19 Cases: From Hematopoietic Stem Cell Recruitment and Chemotaxis to Thrombo‐inflammation

Abstract

Graphical 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.

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“…However, it inhibited the expression of hematopoietic stem cells, NK cells, and Mast cells. With the disease progression of COVID-19 patients, the analysis results of this study showed that the number of NK cell cells decreased [ 13 ], the number of Tregs increased [ 14 ], and hematopoietic stem cell decreased [ 15 ], which were consistent with previous research results.…”

“…In addition, hematopoietic stem cells (HSC) can differentiate into immune cells, providing defense against viral infection. SARS-Cov-2 binded to the angiotensin converting enzyme 2 (ACE2) expressed in HSC, which not only blocked the proliferation and differentiation of HSC but also led to the overactivation of Nlrp3 inflammasome, which ultimately became the culprit of “cytokine storm” [ 15 ]. Thus, the normal differentiation of HSC helped suppress COVID-19 infection.…”

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“…Adjacent lung cells are then stimulated through P2RY14 to secrete IL-8, which acts as a chemo-attractant for neutrophils [ 79 ]. It is also possible that UDP-glucose directly stimulates the P2RY14 expressed on neutrophils to attract them to the site of infection [ 79 , 80 ]. Recruited neutrophils sometimes control infection by the production of NETs.…”

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“…Extracellular nucleotides secreted from various tissues or organs play indispensable roles in regulating innate and adaptive immune responses as potent ligands through activating respective purinergic receptors ( 30 ). Several recent studies revealed that GPR105 acted as an essential factor in acute inflammatory responses under the condition of glycogen metabolism dysregulation ( 31 ), which had been regarded as a potential target for the prevention and/or attenuation of ischemic-AKI ( 32 , 33 ). Our previous studies also demonstrated that novel GPR105 antagonists could effectively improve MSU-induced AGA in cell models ( 24 , 34 ), implying the role of GPR105 in mediating immune inflammation.…”