UDP/P2Y6 contributes to enhancing LPS-induced acute lung injury by regulating neutrophil migration

Abstract

Neutrophils play a prominent role in the inflammatory response and are a critical factor in the pathogenesis of acute lung injury (ALI). Despite a deep understanding of neutrophil accumulation in the pulmonary microvasculature during the process of this disease, the regulatory mechanism of neutrophil recruitment remains unclear. This study aimed to explore the functions and signaling pathways of the purinergic receptor P2Y6 in mediating the innate immune response in ALI. P2Y6-deficient mice, bone marrow chimeras, and neutrophilic chimeras were created in this work to explore the function of P2Y6 in ALI. The results indicated that the extracellular nucleotide UDP was released as a dangerous signal and activated P2Y6 to promote the inflammatory response and pulmonary damage during the process of ALI. P2Y6 deficiency may mitigate deterioration of this disease, including reduced ALI-related inflammatory factor release and immune cell invasion. Bone marrow and neutrophil chimeras and adoptive transfer in mice showed that P2Y6 expression on neutrophils contributed to neutrophil infiltration into lung tissues induced by UDP. Further work indicated that P2Y6 was involved in the neutrophil migration capability through the ErK signaling pathway by mediating the deformation of F-actin filaments and pseudopodia formation during cell recruitment to pulmonary tissue. Here, we provide evidence for the mechanism by which the purinergic receptor P2Y6 contributes to ALI development by regulating neutrophil infiltration into lung tissues. These data indicated that P2Y6 might be a potential therapeutic target for the treatment of this acute severe disease.