Platelet Cxcl7 And Cxcl4 Inhibit Chemokine Scavenging And Improve Innate Immunity To Bacterial Infection

Abstract We recently demonstrated the critical role of CXCL5 in chemokine scavenging, neutrophil homeostasis and host defense to bacterial pneumonia. Here we generated Cxcl7-/- mice and found that Cxcl7 deletion also disrupted expression of CXCL4 and CXCL5, but did not affect expression of two other neutrophil chemokines, CXCL1 and CXCL2. Cxcl4, 7, 5 form a conserved genomic locus (14.5 kb in length) in both human and mice, suggesting their importance during evolution. Heparin treatment of blood led to over 10-fold more plasma CXCL4, but comparable plasma CXCL7 as compared to PBS treatment. In addition, the inactive PPBP form of murine CXCL7 showed considerable binding affinity with red cell DARC. We further delineated the role of CXCL7 and CXCL4 by comparing the phenotypes of Cxcl7-/- and Cxcl5-/- mice. CXCL7 and CXCL4 inhibit chemokine scavenging not only in blood, but also in tissues, and platelet-derived CXCL7 is present in alveolar space and peritoneum. In CXCL1- and nebulized LPS-induced acute lung inflammation models, K. pneumoniae pneumonia and bacteremia models, as compared to Cxcl5-/- mice, Cxcl7-/- mice showed attenuated neutrophil chemokine levels in tissues and blood, decreased neutrophil influx to the lung, and impaired innate immunity. This study is the first to reveal the central role of homeostatic CXCL7 and CXCL4 in increasing chemokine levels in blood and tissues, and potentiating neutrophil transmigration during inflammation and infection.