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)