Elucidating the mechanism of neutrophil-mediated lung injury in sepsis and the role of CD11d/CD18 integrin on this process

Abstract

Abstract Sepsis is the leading cause of death in intensive care unit (ICU) and the most expensive condition treated in the US, without a specific therapy yet available. Acute lung injury (ALI) is one of the most significant organ injuries in sepsis, resulting from massive migration of neutrophils to the lung, but the exact mechanism is not known. β2 (CD18) integrin family [consisting of αLβ2 (CD11a/CD18), αMβ2 (CD11b/CD18), αXβ2 (CD11c/CD18) and αDβ2 (CD11d/CD18)] and its counter-receptor on the endothelium, ICAM-1 (CD54), are critical for neutrophil migration, but their role in ALI is not yet delineated. Using a murine model of sepsis induced by cecal ligation and puncture (CLP) surgery, we showed decreased neutrophil levels and attenuated injury in the lung of β2−/− and ICAM-1−/− mice at 12h post-CLP, suggesting the importance of β2 integrins in this process. In addition, we observed decreased neutrophil levels and attenuated injury in the lung of αDβ2−/− mice but not in the lung of αLβ2−/− and αMβ2−/− mice, suggesting that αDβ2 has an orchestrating role in sepsis-induced ALI. In support, we found increased αDβ2 expression levels on neutrophils both in the lung and blood of WT mice as sepsis progressed. RNAseq analysis in neutrophils from blood and lung of WT and αDβ2−/− mice showed that αDβ2 mediates neutrophil migration to the lung through pathways associated with antigen presentation, apoptosis and NOD-like receptor signaling. αDβ2−/− neutrophils had also less Cxcr2, Ltb4r1 and Dhrs9 expression, associated with neutrophil migration and the retinoic acid pathway. Taken together, our results suggest a mechanism for ALI in sepsis in which αDβ2 integrin has a major role and could be a novel target for therapeutic intervention. The Anesthesia Research Distinguished Trailblazer Award, Boston Children's Hospital The William F. Milton Fund, Harvard University