ALDH2 deficiency in pancreatic acinar cells aggravates acute pancreatitis by promoting NLRP3 inflammasome activation through autophagy

Abstract

BACKGROUND

Acute pancreatitis (AP), a common acute gastrointestinal inflammation with rising incidence, imposes a substantial disease burden. However, targeted therapies for this condition remain elusive.

AIM

To investigate the role of aldehyde dehydrogenase 2 (ALDH2) in AP.

METHODS

Transcriptomic analysis of pancreatic tissue from murine AP models was conducted to identify dysregulated pathways. The porcine AP model was used as a preclinical model to evaluate ALDH2, nod-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, and autophagy-related markers. Pancreatic acinar cell-specific ALDH2 knockout (Aldh2^fl/flCela1-Cre) mice and ALDH2-specific siRNA transfected MPC-83 cells were created to interfere with ALDH2 expression. Rapamycin, ALDH2 agonist Alda-1, and chloroquine were used to investigate the role of autophagy in ALDH2-mediated regulation of the NLRP3 inflammasome.

RESULTS

We demonstrated that genes differentially expressed during AP were enriched in inflammatory immune and autophagy-related pathways. In porcine AP models, the severity of AP was associated with increase of ALDH2, NLRP3, apoptosis associated speck-like protein (ASC), and caspase-1 expression, along with reduced ALDH2 enzymatic activity and accumulation of autophagic substrates, as evidenced by elevated P62 and microtubule-associated protein light chain 3B-II levels and the presence of aggregated autophagic vesicles. Using in vivo murine and in vitro cellular AP models, we found that ALDH2 deficiency in pancreatic acinar cells further exacerbated AP, enhanced NLRP3 inflammasome activation, and aggravated autophagic substrate accumulation. Moreover, in cellular AP models, ALDH2 deficiency attenuated rapamycin-induced NLRP3 inflammasome inhibition. Conversely, Alda-1 reduced NLRP3 inflammasome activation, and this effect was reversed by chloroquine co-treatment, indicating that this reduction is autophagy-dependent.

CONCLUSION

In summary, ALDH2 deficiency in pancreatic acinar cells aggravates AP by exacerbating autophagic substrate accumulation and NLRP3 inflammasome activation, whereas ALDH2 activation reduces inflammasome components in an autophagy-dependent manner, suggesting this pathway as a potential therapeutic direction in AP.

Keywords: Acute pancreatitis; Aldehyde dehydrogenase 2; Autophagy; Nod-like receptor family pyrin domain-containing 3 inflammasome; Pancreatic acinar cell

Core Tip: Using caerulein-induced mouse and endoscope-based porcine acute pancreatitis (AP) models, this study found aldehyde dehydrogenase 2 (ALDH2) expression in pancreatic acinar cells increased while activity decreased, accompanied by autophagic substrate accumulation and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation. During AP, ALDH2 deficiency in pancreatic acinar cells exacerbated autophagic substrate accumulation and NLRP3 inflammasome activation in vivo and in vitro. ALDH2 deficiency attenuated rapamycin's inhibition of NLRP3 inflammasome activation, while ALDH2 agonist Alda-1 reduced inflammasome components in an autophagy-dependent manner, as evidenced by chloroquine reversal. These findings link ALDH2, autophagy, and NLRP3 inflammasome regulation in pancreatic acinar cells.