Cytosolic Proliferating Cell Nuclear Antigen (PCNA) interacts with S100A8 and controls an inflammatory subset of neutrophils in COVID-19
Formiga, R.; Pesenti, L.; Ladjemi, M. Z.; Andrieu, M.; Many, S.; Karunanithy, V.; Bailly, K.; Dhote, T.; Starick, M.; Lummertz da Rocha, E.; Puig Lombardi, E.; Frachet, P.; Granger, V.; de Chaisemartin, L.; Chollet-Martin, S.; Mouthon, L.; Spiller, F.; Hosmalin, A.; Hurtado-Nedelec, M.; Martin, C.; Pene, F.; Burgel, P.-R.; Tourneur, L.; Witko-Sarsat, V.
Show 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-CD62Llow activated 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.
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