Circular RNA circVAPA modulates macrophage pyroptosis in sepsis‐induced acute lung injury through targeting miR‐212‐3p/Sirt1/Nrf2/NLRP3 axis

Abstract Sepsis‐induced acute lung injury (ALI) is an inflammatory condition involving the pyroptosis of macrophages. This study investigated the role of circular RNA hsa_circ_0006990 (circVAPA) in regulating macrophage pyroptosis in ALI and the underlying mechanisms. The expression pattern of circVAPA was examined in the mouse model of ALI and in the LPS‐treated RAW264.7 macrophage cell line. Lung tissue damage was evaluated by haematoxylin and eosin staining, immunohistochemistry and a myeloperoxidase activity assay. The molecular mechanisms were investigated by luciferase reporter assay, western blot, RT‐qPCR and ELISA. circVAPA was down‐regulated in the lung tissues of ALI mice and LPS‐induced RAW264.7 cells. circVAPA over‐expression alleviated lung tissue injury and dampened LPS‐induced pyroptosis and Th17‐associated inflammatory responses. miR‐212‐3p was identified as a target of circVAPA, and miR‐212‐3p negatively regulated the expression of Sirt1. Sirt1 knockdown largely abolished the effect of circVAPA over‐expression on pyroptosis. CircVAPA/miR‐212‐3p/Sirt1 axis also regulates Nrf2 and NLRP3 expression upon LPS challenge. By targeting miR‐212‐3p, circVAPA over‐expression negatively regulates the expression of Sirt1 and pyroptosis‐related factors (Nrf2 and NLRP3), which alleviates the inflammatory damages in sepsis‐induced ALI.