Neutrophil transfer of <i>miR-223</i> to lung epithelial cells dampens acute lung injury in mice.

Abstract

Intercellular transfer of microRNAs can mediate communication between critical effector cells. We hypothesized that transfer of neutrophil-derived microRNAs to pulmonary epithelial cells could alter mucosal gene expression during acute lung injury. Pulmonary-epithelial microRNA profiling during coculture of alveolar epithelial cells with polymorphonuclear neutrophils (PMNs) revealed a selective increase in lung epithelial cell expression of microRNA-223 (<i>miR-223</i>). Analysis of PMN-derived supernatants showed activation-dependent release of <i>miR-223</i> and subsequent transfer to alveolar epithelial cells during coculture in vitro or after ventilator-induced acute lung injury in mice. Genetic studies indicated that <i>miR-223</i> deficiency was associated with severe lung inflammation, whereas pulmonary overexpression of <i>miR-223</i> in mice resulted in protection during acute lung injury induced by mechanical ventilation or by infection with <i>Staphylococcus aureus</i> Studies of putative <i>miR-223</i> gene targets implicated repression of poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1) in the <i>miR-223</i>-dependent attenuation of lung inflammation. Together, these findings suggest that intercellular transfer of <i>miR-223</i> from neutrophils to pulmonary epithelial cells may dampen acute lung injury through repression of PARP-1.