Immunothrombolytic monocyte-neutrophil axes dominate the single-cell landscape of human thrombosis and correlate with thrombus resolution

Pekayvaz, Kami ; Kilani, Badr ; Joppich, Markus ; Eivers, Luke ; Brambs, Sophia; Knottenberg, Viktoria; Akgöl, Sezer ; Yue, Keyang; Li, Lukas; Martinez-Navarro, Alejandro ; Kaiser, Rainer ; Meißner, Nina; Schulz, Heiko; Belz, Larissa; Akhalkatsi, Anastassia; Stockhausen, Sven ; Müller, Tonina T. ; Millonig, Simon; Hartelt, Lea; Gold, Christoph; Janjic, Aleksandar ; Polewka, Vivien; Wendler, Franziska; Droste zu Senden, Augustin; Titova, Anna; Leunig, Alexander ; Voelkl, Michael; Engelmann, Bernd; Hernandez Petzsche, Moritz R.; Boeckh-Behrens, Tobias; Liebig, Thomas; Winning, Sandra; Fandrey, Joachim; Dichgans, Martin ; Enard, Wolfgang ; Zimmer, Ralf ; Tiedt, Steffen ; Massberg, Steffen ; Nicolai, Leo und Stark, Konstantin (2025): Immunothrombolytic monocyte-neutrophil axes dominate the single-cell landscape of human thrombosis and correlate with thrombus resolution. In: Immunity, Vol. 58, No. 5: pp. 1343-1358

Abstract

Thrombotic diseases remain the major cause of death and disability worldwide, and the contribution of inflammation is increasingly recognized. Thromboinflammation has been identified as a key pathomechanism, but an unsupervised map of immune-cell states, trajectories, and intercommunication at a single-cell level has been lacking. Here, we reveal innate leukocyte substates with prominent thrombolytic properties by employing single-cell omics measures on human stroke thrombi. Using in vivo and in vitro thrombosis models, we propose a pro-resolving monocyte-neutrophil axis, combining two properties: (1) NR4A1hi non-classical monocytes acquire a thrombolytic and neutrophil-chemoattractive phenotype, and (2) blood neutrophils are thereby continuously recruited to established thrombi through CXCL8-CXCR1 and CXCR2 and adopt a hypoxia-induced thrombus-resolving urokinase receptor (PLAUR)+ phenotype. This immunothrombolytic axis results in thrombus resolution. Together, with this immune landscape of thrombosis, we provide a valuable resource and introduce the concept of “immunothrombolysis” with broad mechanistic and translational implications at the crossroad of inflammation and thrombosis.

• Item Type: Journal article
• Faculties: Mathematics, Computer Science and Statistics > Computer Science; Biology > Department Biology II; Medicine > Institute of Pathology; Medicine > Munich Cluster for Systems Neurology (SyNergy); Medicine > Institute for Stroke and Dementia Research (ISD); Medicine > Medical Center of the University of Munich > Medical Clinic and Outpatient Clinic I (Cardiology); Medicine > Medical Center of the University of Munich > Medical Clinic and Outpatient Clinic III (Oncology); Medicine > Medical Center of the University of Munich > Institute of Laboratory Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1074-7613
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198