Abstract Body: Background: Atherosclerosis is a leading cause of cardiovascular disease. CXCL5 (ENA-78), a chemokine regulating neutrophil migration, angiogenesis, and tissue remodeling via CXCR2, also functions as an adipokine linking inflammation to metabolic dysfunction. Elevated circulating CXCL5 levels inversely correlate with coronary artery disease burden, highlighting its potential as a biomarker and therapeutic target. Preclinical models show CXCL5 upregulation early in atherosclerosis, with anti-CXCL5 antibodies increasing disease burden. This may be due to CXCL5's atheroprotective effects in controlling macrophage foam cell formation and promoting cholesterol efflux. This study investigates the effects of exogenous CXCL5 administration on atherosclerotic plaque formation.
Methods: Male CXCL5 haploinsufficient/ApoE knockout (KO) mice (n=16) were fed a normal chow diet for 10 weeks, followed by a high-fat diet (HFD; 0.2% cholesterol, 42% calories from fat) for 6 weeks to induce atherosclerosis. Afterward, mice received continuous intravenous infusion of human CXCL5 (90 ng/hr; n=8) or Ringer's solution (control; n=8) via subcutaneous osmotic pumps inserted into the jugular vein. Mice remained on the HFD for 6 additional weeks before euthanasia. Aortas and aortic root samples were collected for histological analysis, including H&E staining for tissue morphology, CD68 for macrophage quantification, and Oil Red O for plaque formation and lipid content.
Results: This is the first report of CXCL5 delivery via intravenous osmotic pump. Long-term infusion caused no mortality or adverse effects. Body weights were similar between control (29.6 g) and CXCL5-treated mice (31.0 g; p=0.385), with no differences in liver (p=0.843) or white adipose tissue (WAT; p=0.733) weights. Circulating CXCL5 levels increased 5-fold with infusion. We expect to observe reduced lesion size, decreased foam cell formation, and improved plaque stability.
Conclusions: This study explores CXCL5's role in atherosclerosis and its therapeutic potential. Pending histological analyses will evaluate its anti-atherogenic effects and provide insights into CXCL5-mediated cellular mechanisms in plaque formation and stability.