Senescent endothelial cells promote pathogenic neutrophil trafficking in inflamed tissues

Cellular senescence is a hallmark of advanced age and a major instigator of numerous inflammatory pathologies. While endothelial cell (EC) senescence is aligned with defective vascular functionality, its impact on fundamental inflammatory responses in vivo at single-cell level remain unclear. To directly investigate the role of EC senescence on dynamics of neutrophil-venular wall interactions, we applied high resolution confocal intravital microscopy to inflamed tissues of an EC-specific progeroid mouse model, characterized by profound indicators of EC senescence. Progerin-expressing ECs supported prolonged neutrophil adhesion and crawling in a cell autonomous manner that additionally mediated neutrophil-dependent microvascular leakage. Transcriptomic and immunofluorescence analysis of inflamed tissues identified elevated levels of EC CXCL1 on progerin-expressing ECs and functional blockade of CXCL1 suppressed the dysregulated neutrophil responses elicited by senescent ECs. Similarly, cultured progerin-expressing human ECs exhibited a senescent phenotype, were pro-inflammatory and prompted increased neutrophil attachment and activation. Collectively, our findings support the concept that senescent ECs drive excessive inflammation and provide new insights into the mode, dynamics, and mechanisms of this response at single-cell level.A murine model of endothelial cell (EC) senescence reveals that exacerbated generation of EC-derived CXCL1 is a driver of pathogenic neutrophil interactions with senescent endothelium at sites of inflammation.Senescent progerin-expressing ECs support aberrant neutrophil adhesion in inflamed tissues.Senescent ECs promote neutrophil-dependent vascular leakage.The pro-inflammatory effects of senescent ECs is mediated by excessive EC production of CXCL1.A murine model of endothelial cell (EC) senescence reveals that exacerbated generation of EC-derived CXCL1 is a driver of pathogenic neutrophil interactions with senescent endothelium at sites of inflammation.