Neutrophil purinergic signaling as a regulator of platelet interactions

• Grant number: 22/06868-1
• Support Opportunities: Scholarships abroad - Research
• Start date: December 15, 2022
• End date: December 14, 2023
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Bruna de Moraes Mazetto Fonseca
• Grantee: Bruna de Moraes Mazetto Fonseca
• Host Investigator: Jason Knight
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: University of Michigan, United States

Abstract

Antiphospholipid syndrome (APS) is a leading acquired cause of thrombosis and late-term pregnancy loss. Lifelong anticoagulation is so far the only treatment proven to reduce vascular complications of APS. Despite this, 1 in 5 patients will still experience a breakthrough thrombotic event. Anticoagulants also do little to mitigate the occlusive microangiopathy that leads to organ deterioration over time. How to combat anticoagulant-resistant manifestations of APS is unknown. Our group has found that neutrophil extracellular traps-NETs, tangles of chromatin and microbicidal proteins expelled from activated neutrophils via "NETosis"-are required for APS-associated thrombosis. It is known that dying cells release purine nucleotides such as ATP and ADP, which engage cell surface receptors to trigger inflammation and coagulation. As a counterpoint, many cells also express the surface ectonucleotidases CD39 and CD73, which catalyze the stepwise phosphohydrolysis of ATP into adenosine-thereby creating an anti-inflammatory, antithrombotic "halo" around the cell. CD73-generated adenosine restrains NET release by activating surface adenosine A2A receptors (A2AR) and thereby boosting intracellular cAMP, with implications for lupus, APS, and COVID-19. The hypothesis is that manipulation of the CD73-A 2A R-cAMP axis will restore neutrophil homeostasis in APS. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

TSOU, PEI-SUEN; ALI, RAMADAN A.; LU, CHENYANG; SULE, GAUTAM; CARMONA-RIVERA, CARMELO; LUCOTTI, SERENA; IKARI, YUZO; WU, QI; CAMPBELL, PHILLIP L.; GURREA-RUBIO, MIKEL; et al. Soluble CD13 is a potential mediator of neutrophil-induced thrombogenic inflammation in SARS-CoV-2 infection. JCI INSIGHT, v. 10, n. 9, p. 21-pg., 2025-05-08. (22/06868-1)