Platelet C5aR1 Aggravates Myocardial Infarction through Platelet-Neutrophil Interactions and CXCL4-Dependent NET Release

Schommer, N.; Zhang, S.; Nording, H.; Sauter, M.; von Esebeck, J.; Schilf, P.; Sadik, C. D.; Schanze, N.; Gauchel, N.; Hamad, M. A.; Krauel, K.; Burkhard, N.; Heger, L. A.; Langer, H. F.; Duerschmied, D.

doi:10.64898/2026.01.12.699090

bioRxiv · 10.64898/2026.01.12.699090

Platelet C5aR1 Aggravates Myocardial Infarction through Platelet-Neutrophil Interactions and CXCL4-Dependent NET Release

Schommer, N.·Zhang, S.·Nording, H.·Sauter, M.·von Esebeck, J.·Schilf, P.·Sadik, C. D.·Schanze, N.·Gauchel, N.·Hamad, M. A.·Krauel, K.·Burkhard, N.·Heger, L. A.·Langer, H. F.·Duerschmied, D.

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Abstract

Platelet activation is a central driver of myocardial infarction. The complement anaphylatoxin C5a is abundantly generated during myocardial infarction, and its receptor C5aR1 is highly expressed on platelets. However, the functional role of platelet C5aR1 in myocardial infarction (MI) remains unknown. Here, we show that platelet&[ndash]expressed C5aR1 critically amplifies thromboinflammatory cardiac injury by promoting platelet&[ndash]mediated neutrophil activation after MI. Platelet&[ndash]specific C5aR1 deletion reduced infarct size, fibrosis, and adverse remodeling while enhancing neovascularization and preserving cardiac function. Mechanistically, cell&[ndash]specific C5aR1 deletion markedly reduced myocardial platelet&[ndash]neutrophil accumulation and neutrophil extracellular trap (NET) formation, while circulating platelet&[ndash]neutrophil complexes were increased. Ex vivo, C5a&[ndash]stimulated platelets robustly induced NET release from neutrophils in a platelet C5aR1&[ndash] and CXCL4&[ndash]dependent manner, whereas platelets lacking C5aR1 failed to trigger NET formation. Pharmacological C5aR1 inhibition with PMX205 phenocopied the genetic platelet&[ndash]specific deletion, resulting in comparable cardioprotection. Together, these findings identify platelet C5aR1 as a druggable target of platelet&[ndash]neutrophil&[ndash]NET signaling that exacerbates myocardial injury and limits reparative healing after MI, highlighting platelet C5aR1 as a potential therapeutic approach to restrain thromboinflammation.

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Schommer, N., Zhang, S., Nording, H., Sauter, M., von Esebeck, J., Schilf, P., Sadik, C. D., Schanze, N., Gauchel, N., Hamad, M. A., Krauel, K., Burkhard, N., Heger, L. A., Langer, H. F., Duerschmied, D.. 2026-01-12. Platelet C5aR1 Aggravates Myocardial Infarction through Platelet-Neutrophil Interactions and CXCL4-Dependent NET Release. https://doi.org/10.64898/2026.01.12.699090

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