STUDY OF THE ROLE OF VMP1 IN INFLAMMASOME ACTIVATION DURINGACUTE PANCREATITIS

TORASSO, L.; SANTORUN, C.; RENNA, F. J.; VACCARO, M. I.; ALEJANDRO JAVIER ROPOLO

CIUDAD AUTONOMA DE BUENOS AIRES

Congreso; VI INTERNATIONAL CONGRESS IN TRANSLATIONALMEDICINE; 2023

Universidad de Buenos Aires - Embajada de Alemania - Centro Universitario Argentino Alemán - Universidad Nacional de Cuyo

Acute pancreatitis (AP) is a local inflammation that induces systemic inflammatory response syndrome in severe presentations. VMP1 is an autophagy-related protein induced in pancreas during AP. Previously, we demonstrated that VMP1-mediated autophagy is involved in selective degradation of damaged mitochondria, mitophagy, and degradation of zymogen granules activated during AP, zymophagy. Thus, VMP1-mediated autophagy prevents disease severity. The Inflammasome is a multimeric protein complex responsible for the activation of inflammatory responses leading to IL-1β production. NLRP3 is a sensor protein of inflammasome involved in the activation of monocytes and neutrophils that infiltrate pancreas in the AP context. Activation of the inflammasome has been associated with disease severity. Autophagy regulates inflammasome removing NLRP3 components, activators, and cytokines. In this context, we hypothesize that VMP1-mediated autophagy modulates the inflammatory process by regulating inflammasome activity. To assess if VMP1 is implicated in inflammasome activation we used monocyte cell lines. We worked with THP-1 and THP-1-ASC-GFP cells activated by LPS+ATP. We found out that NLRP3-inflammasome activation increased VMP1 expression and IL-1β production analyzed by western blot. The adaptor molecule ASC links inflammasome sensors to IL-1β production. In THP-1-ASC-GFP cells with no stimulation, no GFP signal was detected. Upon inflammasome activation, ASC-GFP polymerizes, and a green spot was observed under the fluorescence microscope. The expression of ASC-GFP analyzed by western blot was also increased. Interestingly, inhibition of NLRP3 with butyrate induced strong expression of VMP1 and autophagy, evidenced by LC3-II expression by western blot. All these results suggest that VMP1-mediated autophagy regulates NLRP3-inflammasome activation. This is another possible mechanism by which VMP1-mediated autophagy would reduce the severity of AP.