PI3Kgamma promotes neutrophil extracellular trap formation by noncanonical pyroptosis in abdominal aortic aneurysm

Abstract

AbstractBackgroundAbdominal aortic aneurysm (AAA) is one of the most life-threatening cardiovascular diseases while currently lacks effective drug treatment. NETs formation has been proved to be crucial trigger of AAA, so finding its upstream regulatory targets is the key to discovering therapeutic agents for AAA.Methods and Resultswe reveal that PI3Kgmma (PI3Kγ) is an upstream signal that regulates NETs formation. Inhibition of PI3Kγ reduces the expression of NETs and reduces inflammation in the aortic wall, thereby significantly ameliorating AAA. However, the mechanism of NETs formation regulated by PI3Kγ has not been fully elucidated. Using isolated bone marrow neutrophils, we show that PI3Kγ deficiency inactivates the noncanonical pyroptosis pathway (Capase11/GSDMD) to inhibit NETs expression, and subsequently found that PI3Kγ regulation of noncanonical pyroptosis via anchoring PKA is dependent on cAMP/PKA signaling, but not on classical PI3K/AKT signaling.ConclusionsOur research uncovers the role and mechanism of PI3Kγ in AAA development and provides insights into AAA therapy from the perspective of NETs formation.