tetano
Editor, Senior Moderator
Proc Natl Acad Sci U S A
. 2025 Oct 28;122(43):e2503667122.
doi: 10.1073/pnas.2503667122. Epub 2025 Oct 21. Cytosolic proliferating cell nuclear antigen (PCNA) orchestrates neutrophil hyperactivation in COVID-19
Rodrigo de Oliveira Formiga[SUP] 1 2 3 [/SUP], Lucie Pesenti[SUP] 1 2 [/SUP], François Chable de la Héronnière[SUP] 1 2 [/SUP], Maha Zohra Ladjemi[SUP] 1 2 [/SUP], Darko Stojkov[SUP] 4 [/SUP], Shida Yousefi[SUP] 4 [/SUP], Philippe Frachet[SUP] 5 [/SUP], Lisa Krafft[SUP] 6 [/SUP], Laura Tiberio[SUP] 7 [/SUP], Daniela Bosisio[SUP] 7 [/SUP], Muriel Andrieu[SUP] 1 2 [/SUP], Souganya Many[SUP] 1 2 [/SUP], Vaarany Karunanithy[SUP] 1 2 [/SUP], Karine Bailly[SUP] 1 2 [/SUP], Théo Dhôte[SUP] 1 2 [/SUP], Giovanni Saraceni-Tasso[SUP] 1 2 [/SUP], Manon Castel[SUP] 1 2 [/SUP], Christophe Rousseau[SUP] 1 2 [/SUP], Marick Rodrigues Starick[SUP] 3 [/SUP], Edroaldo Lummertz da Rocha[SUP] 8 [/SUP], Emilia Puig Lombardi[SUP] 9 [/SUP], Cicero José Luíz Dos Ramos Almeida[SUP] 10 [/SUP], Anderson Dos Santos Ramos[SUP] 10 [/SUP], Fernando Queiroz Cunha[SUP] 10 [/SUP], José Carlos Alves-Filho[SUP] 10 [/SUP], Natália Ribeiro Cabacinha Nóbrega[SUP] 11 [/SUP], Matheus Rodrigues Gonçalves[SUP] 12 [/SUP], Celso Martins Queiroz-Junior[SUP] 11 [/SUP], Viviane Lima Batista[SUP] 12 [/SUP], Mauro Martins Teixeira[SUP] 13 [/SUP], Vanessa Granger[SUP] 14 15 [/SUP], Sylvie Chollet-Martin[SUP] 14 15 [/SUP], Luc De Chaisemartin[SUP] 14 15 [/SUP], Luc Mouthon[SUP] 1 16 [/SUP], Anne Hosmalin[SUP] 1 2 [/SUP], Margarita Hurtado-Nedelec[SUP] 17 [/SUP], Clémence Martin[SUP] 1 2 18 [/SUP], Fernando Spiller[SUP] 3 [/SUP], Hans-Uwe Simon[SUP] 4 19 [/SUP], Nicolas Tamassia[SUP] 20 [/SUP], Marco Antonio Cassatella[SUP] 20 [/SUP], Frédéric Pène[SUP] 1 2 21 [/SUP], Thomas Vogl[SUP] 6 [/SUP], Pierre-Regis Burgel[SUP] 1 2 18 [/SUP], Vivian Vasconcelos Costa[SUP] 11 [/SUP], Véronique Witko-Sarsat[SUP] 1 2 [/SUP]
Affiliations
Neutrophils are central mediators of the hyperinflammatory response in severe SARS-CoV-2 infection. We report elevated cytosolic levels of proliferating cell nuclear antigen (PCNA) in neutrophils from patients with severe and critical COVID-19, correlating with enhanced NADPH oxidase-dependent reactive oxygen species (ROS) generation and neutrophil extracellular trap (NET) formation. Using T2AA, a small-molecule inhibitor of the PCNA scaffold, we demonstrate potent suppression of NADPH oxidase activation and NET release, particularly in response to SARS-CoV-2 RNA. Mechanistically, we identify a previously unrecognized interaction between PCNA and the heterodimeric S100A8/S100A9 (calprotectin), predominantly enriched in CD16[SUP]high[/SUP]CD62L[SUP]low[/SUP] neutrophils expanded during COVID-19. PCNA binds the dimeric S100A8/S100A9 complex mediated via S100A8 subunit with micromolar affinity, and this interaction is abrogated by tetramerization, suggesting regulation by intracellular calcium. Disruption of this complex by T2AA inhibited ROS production in an S100A8/S100A9-dependent manner, implicating calprotectin as a functional regulator of neutrophil activation. In a betacoronavirus mouse model, T2AA treatment attenuated lung inflammation, reduced NET and calprotectin levels, and shifted pulmonary neutrophils away from hyperactivated and immunosuppressive phenotypes, consistent with immune reprogramming toward resolution. These findings establish cytosolic PCNA as a central scaffold in neutrophil hyperactivation during COVID-19 and highlight its pharmacological disruption as a promising host-directed strategy to limit inflammation and prevent organ damage.
Keywords: COVID-19; PCNA; neutrophils.
. 2025 Oct 28;122(43):e2503667122.
doi: 10.1073/pnas.2503667122. Epub 2025 Oct 21. Cytosolic proliferating cell nuclear antigen (PCNA) orchestrates neutrophil hyperactivation in COVID-19
Rodrigo de Oliveira Formiga[SUP] 1 2 3 [/SUP], Lucie Pesenti[SUP] 1 2 [/SUP], François Chable de la Héronnière[SUP] 1 2 [/SUP], Maha Zohra Ladjemi[SUP] 1 2 [/SUP], Darko Stojkov[SUP] 4 [/SUP], Shida Yousefi[SUP] 4 [/SUP], Philippe Frachet[SUP] 5 [/SUP], Lisa Krafft[SUP] 6 [/SUP], Laura Tiberio[SUP] 7 [/SUP], Daniela Bosisio[SUP] 7 [/SUP], Muriel Andrieu[SUP] 1 2 [/SUP], Souganya Many[SUP] 1 2 [/SUP], Vaarany Karunanithy[SUP] 1 2 [/SUP], Karine Bailly[SUP] 1 2 [/SUP], Théo Dhôte[SUP] 1 2 [/SUP], Giovanni Saraceni-Tasso[SUP] 1 2 [/SUP], Manon Castel[SUP] 1 2 [/SUP], Christophe Rousseau[SUP] 1 2 [/SUP], Marick Rodrigues Starick[SUP] 3 [/SUP], Edroaldo Lummertz da Rocha[SUP] 8 [/SUP], Emilia Puig Lombardi[SUP] 9 [/SUP], Cicero José Luíz Dos Ramos Almeida[SUP] 10 [/SUP], Anderson Dos Santos Ramos[SUP] 10 [/SUP], Fernando Queiroz Cunha[SUP] 10 [/SUP], José Carlos Alves-Filho[SUP] 10 [/SUP], Natália Ribeiro Cabacinha Nóbrega[SUP] 11 [/SUP], Matheus Rodrigues Gonçalves[SUP] 12 [/SUP], Celso Martins Queiroz-Junior[SUP] 11 [/SUP], Viviane Lima Batista[SUP] 12 [/SUP], Mauro Martins Teixeira[SUP] 13 [/SUP], Vanessa Granger[SUP] 14 15 [/SUP], Sylvie Chollet-Martin[SUP] 14 15 [/SUP], Luc De Chaisemartin[SUP] 14 15 [/SUP], Luc Mouthon[SUP] 1 16 [/SUP], Anne Hosmalin[SUP] 1 2 [/SUP], Margarita Hurtado-Nedelec[SUP] 17 [/SUP], Clémence Martin[SUP] 1 2 18 [/SUP], Fernando Spiller[SUP] 3 [/SUP], Hans-Uwe Simon[SUP] 4 19 [/SUP], Nicolas Tamassia[SUP] 20 [/SUP], Marco Antonio Cassatella[SUP] 20 [/SUP], Frédéric Pène[SUP] 1 2 21 [/SUP], Thomas Vogl[SUP] 6 [/SUP], Pierre-Regis Burgel[SUP] 1 2 18 [/SUP], Vivian Vasconcelos Costa[SUP] 11 [/SUP], Véronique Witko-Sarsat[SUP] 1 2 [/SUP]
Affiliations
- PMID: 41118208
- DOI: 10.1073/pnas.2503667122
Neutrophils are central mediators of the hyperinflammatory response in severe SARS-CoV-2 infection. We report elevated cytosolic levels of proliferating cell nuclear antigen (PCNA) in neutrophils from patients with severe and critical COVID-19, correlating with enhanced NADPH oxidase-dependent reactive oxygen species (ROS) generation and neutrophil extracellular trap (NET) formation. Using T2AA, a small-molecule inhibitor of the PCNA scaffold, we demonstrate potent suppression of NADPH oxidase activation and NET release, particularly in response to SARS-CoV-2 RNA. Mechanistically, we identify a previously unrecognized interaction between PCNA and the heterodimeric S100A8/S100A9 (calprotectin), predominantly enriched in CD16[SUP]high[/SUP]CD62L[SUP]low[/SUP] neutrophils expanded during COVID-19. PCNA binds the dimeric S100A8/S100A9 complex mediated via S100A8 subunit with micromolar affinity, and this interaction is abrogated by tetramerization, suggesting regulation by intracellular calcium. Disruption of this complex by T2AA inhibited ROS production in an S100A8/S100A9-dependent manner, implicating calprotectin as a functional regulator of neutrophil activation. In a betacoronavirus mouse model, T2AA treatment attenuated lung inflammation, reduced NET and calprotectin levels, and shifted pulmonary neutrophils away from hyperactivated and immunosuppressive phenotypes, consistent with immune reprogramming toward resolution. These findings establish cytosolic PCNA as a central scaffold in neutrophil hyperactivation during COVID-19 and highlight its pharmacological disruption as a promising host-directed strategy to limit inflammation and prevent organ damage.
Keywords: COVID-19; PCNA; neutrophils.