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.
Keywords: immune landscape; immune-cell plasticity; immunothrombolysis; immunothrombosis; immunothrombotic dysregulation; innate immunity; monocytes; multi-omics; neutrophils; organ ischemia; single-cell; stroke; thromboinflammation; thrombosis; thrombus resolution.
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