CXCL5-CXCR2 axis mediates myocardial ischemia/reperfusion injury by inducing infiltration of myeloid-derived macrophages and neutrophils.

BACKGROUND: Myeloid cell-associated immune responses play a critical role in the pathogenesis of myocardial ischemia/reperfusion (MI/R) injury. Chemokine receptor CXCR2 is expressed mainly in myeloid cells, including neutrophils and macrophages, and is crucial for regulating immune homeostasis. However, the roles of CXCL5 and its receptor CXCR2 in MI/R injury remain unknown. METHODS: To determine the functional significance of CXCL5-CXCR2 axis in MI/R injury, we employed genetic deletion of CXCL5, myeloid-specific deletion of CXCR2, and pharmacological blockade of CXCR2. Cardiac function was evaluated by echocardiography. Myocardial infarct size, apoptosis, and fibrosis were assessed by histological staining. Inflammatory cell infiltration was examined using flow cytometry and immunohistochemistry. Protein and gene expression of signaling mediators and inflammatory markers were analyzed using microarray, qPCR, and immunoblotting. Moreover, circulating CXCR2+ cells and chemokine levels were measured in blood from patients with ST-segment elevation myocardial infarction (STEMI) and controls using flow cytometry and enzyme-linked immunosorbent assay. RESULTS: CXCL5 and CXCR2 expression and the percentage of CXCR2+ immune cells were increased in the heart after I/R injury. CXCL5 deficiency, myeloid-specific deletion of CXCR2, and CXCR2 inhibition improved cardiac function and reduced cardiomyocyte apoptosis, inflammation, oxidative stress, and fibrosis. These protective effects were associated with decreased infiltration of macrophages and neutrophils. Additionally, circulating CD14+ CD16+ CXCR2+ monocytes, CD15+ CD11b+ CXCR2+ neutrophils, and chemokine levels were significantly higher in STEMI patients than in controls. CONCLUSION: The CXCL5-CXCR2 axis represents a promising therapeutic target for MI/R injury and early post-infarct remodeling.