Krüppel-like Factor 5 Plays an Important Role in the Pathogenesis of Chronic Pancreatitis

SIMPLE SUMMARY: This report shows that KLF5 plays a crucial role in the progression of chronic pancreatitis to pre-neoplastic precursor lesions. Notably, the deletion of Klf5 from pancreatic acinar cells by itself or in the context of activating KRAS mutation resulted in a significant reduction in inflammatory and stromal activation and, thus, inhibition of chronic pancreatitis progression. Furthermore, this study demonstrated that KLF5 exerts its role by directly activating profibrotic and inflammatory cytokines. Using ChIP-PCR, we demonstrated that KLF5 binds directly to the Il1b, Il6, and Tgfb1 gene promoters in vitro and in vivo. Deletion of Klf5 during chronic pancreatitis development and progression resulted in a decrease of several vital chemokines, such as CCL6, CCL11, and CCL21. In summary, we showed that KLF5 regulates inflammatory and fibrotic responses during chronic pancreatitis. ABSTRACT: Chronic pancreatitis results in the formation of pancreatic intraepithelial neoplasia (PanIN) and poses a risk of developing pancreatic cancer. Our previous study demonstrated that Krüppel-like factor 5 (KLF5) is necessary for forming acinar-to-ductal metaplasia (ADM) in acute pancreatitis. Here, we investigated the role of KLF5 in response to chronic injury in the pancreas. Human tissues originating from chronic pancreatitis patients showed increased levels of epithelial KLF5. An inducible genetic model combining the deletion of Klf5 and the activation of Kras(G12D) mutant expression in pancreatic acinar cells together with chemically induced chronic pancreatitis was used. The chronic injury resulted in increased levels of KLF5 in both control and Kras(G12D) mutant mice. Furthermore, it led to numerous ADM and PanIN lesions and extensive fibrosis in the KRAS mutant mice. In contrast, pancreata with Klf5 loss (with or without Kras(G12D)) failed to develop ADM, PanIN, or significant fibrosis. Furthermore, the deletion of Klf5 reduced the expression level of cytokines and fibrotic components such as Il1b, Il6, Tnf, Tgfb1, Timp1, and Mmp9. Notably, using ChIP-PCR, we showed that KLF5 binds directly to the promoters of Il1b, Il6, and Tgfb1 genes. In summary, the inactivation of Klf5 inhibits ADM and PanIN formation and the development of pancreatic fibrosis.