Molecular mechanisms involved in NLRP3 inflammasome regulation in neutrophils

• Grant number: 21/13049-4
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): April 04, 2022
• Effective date (End): April 03, 2023
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Alessandra Pontillo
• Grantee: Vinícius Nunes Cordeiro Leal
• Supervisor: Alexander Weber
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Research place: Eberhard Karls Universität Tübingen, Germany
• Associated to the scholarship: 20/15323-3 - Disregulation of inflammasome' activation in neutrophil and endothelium in response to SARS-Cov-2 and contribution to severe COVID-19, BP.PD

Abstract

Inflammasome activation exacerbates immune response to SARS-CoV-2 possibly contributing to SARS and thrombotic disease in COVID-19 patients. We recently reported that the NLRP3 inflammasome is dramatically activated in neutrophils isolated from severe COVID-19 patients. However up-to-now the exact mechanism of complex activation in SARS-CoV-2 infection remains unclear. COVID-19 patients present increased levels of metalloproteinase (MMP)-9 and peptidylarginine deiminase 4 (PAD4), two molecules involved in neutrophils' activation and neutrophils extracellular trap (NETs) formation. As previously reported, and supported by the direct correlation observed in our patients, PAD4 promotes NLRP3 inflammasome activation which in turn activates MMP-9, suggesting that the complex could represent a central element in COVID-19 neutrophils dysregulation. Here we propose a deeper investigation of the mechanism of NLRP3 inflammasome activation in neutrophils focusing on the Btk and Syk pathway. These two kinases have been previously reported by the hosting laboratory and others to contribute to NLRP3 activation in monocytes and B lymphocytes. Furthermore, the inhibition of Btk, already in use in clinical practice, could represent a pharmaceutical alternative for treatment. (AU)