Background and Purpose: Platelet function during inflammation is dependent on activation by endogenous nucleotides acting on purinergic receptors. The P2Y14 receptor (P2Y14R) has been reported to be expressed on platelets and is involved in leukocyte recruitment during inflammation. However, a role for P2Y14R receptors on platelet function has not yet been determined. Experimental Approach: Platelets obtained from healthy human volunteers were incubated with the P2Y14R agonist, UDP-Glucose (UDP-G), and PPTN, a selective P2Y14R antagonist. Platelet activation was quantified using Ca2+ mobilization, aggregation, and chemotaxis assays. Cooperativity with P2Y1 receptor (P2Y1R) activation was also assessed after stimulation with UDP-G in the presence of MRS2500, a selective P2Y1R antagonist. Key Results: Ca2+ mobilization occurred in platelets after incubation with UDP-G in a concentration-dependent manner, and this was suppressed in platelets treated with PPTN. Platelets did not aggregate, or bind to fibrinogen after incubation with UDP-G. However, platelet chemotaxis towards f-MLP was dependent on P2Y14R stimulation with UDP-G and this was reduced by Rho-GTPase inhibitors. Furthermore, UDP-G induced Ca2+ mobilization and chemotaxis were also inhibited when platelets were pretreated with MRS2500. Conversely, ADP induced Ca2+ mobilization, chemotaxis and aggregation were not affected by the incubation with PPTN. Conclusion and Implications: Platelets can be activated via P2Y14R stimulation to induce chemotaxis but not aggregation. Furthermore, this was dependent on concomitant activation of P2Y1R. Activation of P2Y14Rs on platelets may therefore be relevant during inflammation, but cooperation with P2Y1R activation is required.

Editorial. Platelet purinergic receptors and non-thrombotic diseases.Simon C. Pitchford1* and Dingxin Pan.11Pulmonary Pharmacology Unit, Institute of Pharmaceutical Science, King’s College London, London, UK.*Author for correspondence and reprint requests:Dr Simon PitchfordPulmonary Pharmacology UnitInstitute of Pharmaceutical Science5.43 Franklin Wilkins Building150 Stamford StreetWaterloo CampusKing’s College LondonLondon UKSE1 9NHPhone: +44 2078484266Fax: +44 207 [email protected]

A document by Dingxin (Guest Editor) Pan. Click on the document to view its contents.

The coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 infections has led to substantial unmet need for treatments, many of which will require testing in appropriate animal models of this disease. Vaccine trials are already underway, but there remains an urgent need to find other therapeutic approaches to either target SARS-CoV-2 or the complications arising from viral infection, particularly the dysregulated immune response and systemic complications which have been associated with progression to severe COVID-19. At the time of writing, in vivo studies of SARS-CoV-2 infection have been described using macaques, cats, ferrets, hamsters, and transgenic mice expressing human angiotensin I converting enzyme 2 (ACE2). These infection models have already been useful for studies of transmission and immunity, but to date only partially model the mechanisms implicated in human severe COVID-19. There is therefore an urgent need for development of animal models for improved evaluation of efficacy of drugs identified as having potential in the treatment of severe COVID-19. These models need to recapitulate key mechanisms of COVID-19 severe acute respiratory distress syndrome and reproduce the immunopathology and systemic sequelae associated with this disease. Here, we review the current models of SARS-CoV-2 infection and COVID-19-related disease mechanisms and suggest ways in which animal models can be adapted to increase their usefulness in research into COVID-19 pathogenesis and for assessing potential treatments.