Inhibition of circulating exosomes release with GW4869 mitigates severe acute pancreatitis-stimulated intestinal barrier damage through suppressing NLRP3 inflammasome-mediated pyroptosis

Abstract

Intestinal barrier dysfunction frequently occurs as a complication in cases of severe acute pancreatitis (SAP); however, no effective therapeutic methods are available because the precise mechanism remains obscure. Recent research has elucidated the role of circulating exosomes in the progression of SAP. Therefore, the present study explored whether inhibiting circulating exosomes release would improve intestinal barrier injury triggered via SAP and investigated the possible underlying mechanism. In vivo, we found that circulating exosomes release exhibited a considerable increase in SAP rats than in SO rats, and GW4869, a suppressor of exosomes release, significantly decreased exosomes release in SAP rats. We also observed that GW4869 suppressed NLRP3 inflammasome-mediated pyroptosis within the intestine and alleviated intestinal barrier injury within SAP. Moreover, the inflammatory response and remote organ (kidney and lung) injury associated with SAP improved after GW4869 treatment. In vitro, we confirmed that depletion of exosomes with GW4869 could partially abolish the destructive effects of SAP rat plasma on the viability and barrier function of IEC-6 cells. In summary, our findings show that the suppression of the release of circulating exosomes effectively inhibits the process of pyroptosis mediated by the NOD-like receptor protein 3 (NLRP3) inflammasome and, therefore, mitigates intestinal barrier dysfunction in SAP, suggesting that circulating exosomes may be a potential target for treating SAP.