1. Cytosolic PCNA interacts with S100A8 and controls an inflammatory subset of neutrophils in COVID-19
- Author
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Rodrigo de Oliveira Formiga, Lucie Pesenti, Maha Zohra Ladjemi, Philippe Frachet, Muriel Andrieu, Souganya Many, Vaarany Karunanithy, Karine Bailly, Théo Dhôte, Manon Castel, Christophe Rousseau, Marick Starick, Edroaldo Lummertz da Rocha, Emilia Puig Lombardi, Vanessa Granger, Sylvie Chollet-Martin, Luc De Chaisemartin, Luc Mouthon, Fernando Spiller, Anne Hosmalin, Margarita Hurtado-Nedelec, Clémence Martin, Frédéric Pène, Pierre-Regis Burgel, Léa Tourneur, and Véronique Witko-Sarsat
- Abstract
Neutrophils are key players in the hyperinflammatory response upon SARS-CoV-2 infection. We have previously described that cytosolic proliferating cell nuclear antigen (PCNA) controls neutrophil survival and NADPH oxidase-dependent ROS production. We here show that both PCNA and S100A8 expression and interaction were elevated in neutrophils from patients with COVID-19 compared to healthy donors and this was correlated with disease severity. Increased PCNA expression was accompanied by a decreased apoptosis and increased NADPH-oxidase activity in neutrophils from COVID-19 patients compared to healthy donors. These effects, as well as the interaction between PCNA and S100A8, were potently counteracted by T2 amino alcohol (T2AA), a PCNA inhibitor, demonstrating that the PCNA scaffold orchestrated neutrophil activation. Notably, the interaction between PCNA-S100A8 was more intense in the CD16high-CD62Llowactivated neutrophil subset. We propose that PCNA-S100A8 complex acts as potential driver for neutrophil dysregulation in COVID-19 and show for the first time that the PCNA scaffold is a decisive component of both neutrophil activation and heterogeneity.
- Published
- 2022
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