Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice

Abstract

Chronic pancreatitis is an inflammatory disease that causes progressive destruction of pancreatic acinar cells and, ultimately, loss of pancreatic function. We investigated the role of IκB kinase α (IKKα) in pancreatic homeostasis. Pancreas-specific ablation of IKKα (Ikkα Δpan ) caused spontaneous and progressive acinar cell vacuolization and death, interstitial fibrosis, inflammation, and circulatory release of pancreatic enzymes, clinical signs resembling those of human chronic pancreatitis. Loss of pancreatic IKKα causes defective autophagic protein degradation, leading to accumulation of p62-mediated protein aggregates and enhanced oxidative and ER stress in acinar cells, but none of these effects is related to NF-κB. Pancreas-specific p62 ablation prevented ER and oxidative stresses and attenuated pancreatitis in Ikkα Δpan mice, suggesting that cellular stress induced by p62 aggregates promotes development of pancreatitis. Importantly, downregulation of IKKα and accumulation of p62 aggregates were also observed in chronic human pancreatitis. Our studies demonstrate that IKKα, which may control autophagic protein degradation through its interaction with ATG16L2, plays a critical role in maintaining pancreatic acinar cell homeostasis, whose dysregulation promotes pancreatitis through p62 aggregate accumulation.

Basal autophagy maintains pancreatic acinar cell homeostasis and protein synthesis and prevents ER stress

“…Impaired autophagy can contribute to ER stress by inhibiting degradation of misfolded proteins (15), which undergo ubiquitination and are bound by p62 (27). Indeed, we detected pronounced aggregates/inclusion bodies containing p62 in Atg7 Δpan pancreata (Fig.…”

“…Intrapancreatic trypsin activity was elevated at an early (4 wk) but not at a later (12 wk) time point (Fig. 2D), suggesting that premature, intraacinar, trypsinogen activation is just one of several factors that contribute to this disease (15,16). Collectively, these results indicate that loss of ATG7 triggers pancreatic atrophy, fibrosis, and chronic pancreatitis.…”

“…Conversely, loss of autophagy can result in progressive loss of pancreatic function, which leads to development of pancreatitis as well as regenerative responses that may increase the risk of pancreatic cancer. Ptf1a-Cre; Atg5 F/F ) have demonstrated that insufficient autophagy, at least in mice, can lead to the onset of pancreatitis (15)(16)(17). The mechanisms by which disruption of autophagy triggers pancreatitis are poorly understood.…”

“…Moreover, autophagic flux is reduced during pancreatitis due to defective cathepsinmediated processing of lysosomal proteases (18). Similarly, pancreasspecific ablation of inhibitor of IκB kinase (IKK)α results in acinar damage ranging from vacuole accumulation to chronic pancreatitis (15). IKKα deficiency impairs the completion of autophagy in acinar cells, with accumulation of the chaperon and autophagy substrate ubiquitin-binding protein p62/SQSTM1 as the key pathogenic mechanism (15).…”

“…Similarly, pancreasspecific ablation of inhibitor of IκB kinase (IKK)α results in acinar damage ranging from vacuole accumulation to chronic pancreatitis (15). IKKα deficiency impairs the completion of autophagy in acinar cells, with accumulation of the chaperon and autophagy substrate ubiquitin-binding protein p62/SQSTM1 as the key pathogenic mechanism (15). However, ablation of ATG5 was reported to either inhibit (13) or promote (16) pancreatitis.…”