MiR-144-induced KLF2 inhibition and NF-kappaB/CXCR1 activation promote neutrophil extracellular trap-induced transfusion-related acute lung injury.

Abstract

Transfusion‐related acute lung injury (TRALI) is a clinical syndrome which is associated with the formation of neutrophil extracellular trap (NET). Recent studies have demonstrated the roles of microRNAs (miRNAs) in the pathophysiological process of TRALI. Here, the study focused on the role of miR‐144 and the molecular mechanisms in NET‐induced TRALI. Up‐regulated miR‐144 and under‐expressed KLF2 were determined in patients with TRALI. In the mouse model of a two‐event TRALI induced by intraperitoneal injections with lipopolysaccharide and anti‐H‐2Kd mAb, we determined expression patterns of miR‐144, Krüppel‐like factor 2 (KLF2), chemokine (C‐X‐C motif) receptor 1 (CXCR1) and nuclear factor kappa‐B (NF‐kappaB) p65. The results confirmed that miR‐144 was highly expressed, while KLF2 was poorly expressed in mice with TRALI. Dual‐luciferase reporter gene assay identified that miR‐144 could target KLF2. Using gain‐ and loss‐of‐function approaches, we analysed the effects of miR‐144 and its interaction with KLF2 on TRALI. Enforced expression of miR‐144 was found to aggravate NET‐induced TRALI by down‐regulating KLF2 and activating the NF‐kappaB/CXCR1 signalling pathway in TRALI mice. Collectively, miR‐144‐targeted inhibition of KLF2 and activation of NF‐kappaB/CXCR1 are possible mechanisms responsible for NET‐caused TRALI. These findings aid in the development of therapeutic modalities for the treatment of TRALI.