LIN28B Aggravates the Inflammation in Sepsis-Induced Lung Injury by Stabilizing GATA6 mRNA and Upregulating TRAF6

Sepsis affects more than 19 million people globally each year, and approximately 50% of sepsis patients develop lung injury. Sepsis-triggered lung injury is characterized by over-activation of inflammatory response and the production of large amounts of inflammatory cytokines. However, the underlying mechanisms remain unclear. A cellular model of sepsis-induced lung injury was constructed using lipopolysaccharide (LPS)-exposed human pulmonary microvascular endothelial cells (HPMECs). Cell viability was checked with CCK-8. Apoptosis was checked utilizing flow cytometry and TUNEL staining. TNF-α, IL-1β, and IL-6 levels were measured through ELISA assay. Intermolecular interaction relationships were confirmed by chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), RNA pull down, and dual luciferase reporter assays. LIN28B was increased in the LPS-induced HPMEC. LIN28B knockdown alleviated inflammation and cell injury in LPS-induced HPMEC. LIN28B was bound to GATA6 mRNA and enhanced its mRNA stability, consequently exacerbating LPS-triggered HPMEC inflammation and injury. GATA6 transcriptionally upregulated TRAF6 to promote LPS-induced HPMEC inflammation and injury. The manipulation of the GATA6/TRAF6 axis by LIN28B amplified inflammation and injury in HPMEC prompted by LPS. Our results revealed that LIN28B induced sepsis-triggered lung injury by stabilizing GATA6 mRNA and increasing TRAF6 expression, which might provide novel therapeutic targets for the treatment of sepsis-mediated lung injury.