Reduction in O-GlcNAcylation Mitigates the Severity of Inflammatory Response in Cerulein-Induced Acute Pancreatitis in a Mouse Model.

Mackenzie Moore,Alicia Wong,Megan Beetch,Seokwon Jo,Emilyn U Alejandro,Nandini Avula

doi:10.3390/biology11030347

Mackenzie Moore, Alicia Wong + Show 4 more

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https://doi.org/10.3390/biology11030347

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Abstract

Simple SummaryAcute pancreatitis (AP) is a common disease with significant co-morbidity and increasing global incidence over the past 40 years. Current understanding of molecular underpinnings that facilitates one’s susceptibility to this inflammatory disease is less understood. The protein O-GlcNAc Transferase (OGT) is a cytosolic/nuclear/mitochondrial post-translational glycosylation enzyme that is highly expressed in the pancreas. Here, we propose that OGT, which has been associated with regulating many inflammatory responses such as NFκB signaling, provides the mechanistic link to AP induction and susceptibility. In this study, a mouse model with pancreatic OGT loss was generated and subjected to cerulein, a common pancreatitis inducer. Pancreas OGT-deficient mice exhibited reduced severity of AP, associated with reduced inflammatory markers as well as decreased macrophage population in the pancreas. In conclusion, these data indicate that OGT is a molecular driver that facilitates cerulein-induced AP in vivo. Acute pancreatitis (AP) involves premature trypsinogen activation, which mediates a cascade of pro-inflammatory signaling that causes early stages of pancreatic injury. Activation of the transcription factor κB (NF-κB) and secretion of pro-inflammatory mediators are major events in AP. O-GlcNAc transferase (OGT), a stress-sensitive enzyme, was recently implicated to regulate NF-κB activation and inflammation in AP in vitro. This study aims to determine whether a pancreas-specific transgenic reduction in OGT in a mouse model affects the severity of AP in vivo. Mice with reduced pancreatic OGT (OGTPanc+/−) at 8 weeks of age were randomized to cerulein, which induces pancreatitis, or saline injections. AP was confirmed by elevated amylase levels and on histological analysis. The histological scoring demonstrated that OGTPanc+/− mice had decreased severity of AP. Additionally, serum lipase, LDH, and TNF-α in OGTPanc+/− did not significantly increase in response to cerulein treatment as compared to controls, suggesting attenuated AP induction in this model. Our study reveals the effect of reducing pancreatic OGT levels on the severity of pancreatitis, warranting further investigation on the role of OGT in the pathology of AP.

Highlights

The incidence of acute pancreatitis (AP) has been increasing globally and carries substantial morbidity and mortality as well as increased healthcare utilization and cost [1,2,3]
Normal growth and glucose homeostasis were observed in the OGTPanc+/− mice, given that obesity and hyperglycemia are associated with increased severity of pancreatitis [31]
Pancreas weight was obtained with consideration of saline vs. cerulein treatment, as it was expected that the induction of acute pancreatitis would increase pancreas weight, which was confirmed for both genotypes (controls (Ctrl), p ≤ 0.001; OGTPanc+/−, p ≤ 0.001) (Figure 1G) [32]

Summary

Introduction

The incidence of acute pancreatitis (AP) has been increasing globally and carries substantial morbidity and mortality as well as increased healthcare utilization and cost [1,2,3]. The prevailing theory for the pathophysiology of AP centers around premature activation of trypsin, the key digestive protease synthesized in acinar cells, which triggers a cascade of inappropriate activation of digestive proteases and, pancreatic injury [4,5,6]. Multiple mechanisms contribute to intra-acinar trypsinogen activation and acinar cell death including pathological calcium signaling and organelle dysfunction [7,8,9]. Pathological trypsinogen activation is a major contributor to acinar cell necrosis in AP, it is not required to induce a local or systemic inflammatory response characteristic of the disease [10,11,12]. Mitochondrial dysfunction, autophagy, ER stress, lysosomal function, and inflammatory signaling are reportedly involved. Current literature suggests that trypsin-independent activations of proinflammatory transcription factor nuclear factor κB (NFκB) are major events in AP [13,14,15,16]

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