Induced pluripotent stem cells reduce neutrophil chemotaxis via activating GRK2 in endotoxin-induced acute lung injury.

Background and objectiveWe investigated the effect of induced pluripotent stem cells (iPSCs) in moderating neutrophil chemotaxis in endotoxin-induced acute lung injury (ALI). MethodsMale C57BL/6 mice at 8-12weeks of age were studied. Murine iPSCs were delivered through the tail veins of mice 4h after intratracheal instillation of endotoxin. Lung histopathological findings, neutrophil counts in peripheral blood and bronchoalveolar lavage fluid (BALF), bone marrow (BM) cell distribution, expression of chemokine receptors and regulatory signalling pathways were analysed after 24h. Human neutrophils isolated from acute respiratory distress syndrome patients were used in a cell migration assay. Results iPSCs significantly decreased the histopathological changes of ALI in mice compared to treatment with control cells. Numbers and activity levels of neutrophils in BALF were reduced in iPSC-treated ALI mice. The iPSC therapy restored neutrophil counts in the peripheral blood of ALI mice, but the percentages of mature neutrophils in BM were similar between iPSC-treated and -untreated groups. The iPSCs mediated a downregulation of the chemotactic response to endotoxin by reducing chemokine (C-X-C motif) receptor 2 (CXCR2) expression on mouse peripheral blood neutrophils. This result was confirmed by an in vitro human neutrophil migration assay. In addition, iPSCs or conditioned medium from iPSCs enhanced expression of G protein-coupled receptor kinase 2 (GRK2) on the surface of blood neutrophils in ALI mice. Conclusion iPSCs reduce neutrophil chemotaxis in endotoxin-induced ALI. These effects are associated with an enhancement of GRK2 activity and reduction of CXCR2 expression.