Abstract
Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors, have been found to provide protective effects against several bacterial infectious diseases. Although the use of statins has been shown to enhance antimicrobial treated Helicobacter pylori eradication and reduce H. pylori-mediated inflammation, the mechanisms underlying these effects remain unclear. In this study, in vitro and ex vivo macrophage models were established to investigate the molecular pathways involved in statin-mediated inhibition of H. pylori-induced inflammation. Our study showed that statin treatment resulted in a dose-dependent decrease in intracellular H. pylori burden in both RAW264.7 macrophage cells and murine peritoneal exudate macrophages (PEMs). Furthermore, statin yielded enhanced early endosome maturation and subsequent activation of the autophagy pathway, which promotes lysosomal fusion resulting in degradation of sequestered bacteria, and in turn attenuates interleukin (IL)-1β production. These results indicate that statin not only reduces cellular cholesterol but also decreases the H. pylori burden in macrophages by promoting autophagy, consequently alleviating H. pylori-induced inflammation.
Highlights
Helicobacter pylori is a Gram-negative microaerophilic spirochete that colonizes the human stomach and is estimated to have infected greater than half of the global population (Marshall, 2002)
Both macrophages and H. pylori remained viable, even after treatment with 10 μM simvastatin (Figure 1B). These results indicate that simvastatin reduces the levels of cellular cholesterol in macrophages without affecting cell viability or bacterial survival
We observed increased levels in the conversion of light chain 3 (LC3)-I to LC3-II, as well as increased expression of beclin-1 and p62, in H. pyloriinfected peritoneal exudate macrophages (PEMs) treated with simvastatin, compared to untreated cells. These results suggest that simvastatin treatment reduces cellular cholesterol and promotes H. pylori-induced autophagy in macrophages
Summary
Helicobacter pylori is a Gram-negative microaerophilic spirochete that colonizes the human stomach and is estimated to have infected greater than half of the global population (Marshall, 2002). Persistent H. pylori infection is associated with several upper gastrointestinal disorders such as gastritis, peptic ulcers, and gastric adenocarcinoma (Wroblewski et al, 2010). H. pylori is generally considered an intracellular pathogen, this organism lives in the mucosal layer and tightly adheres to the gastric epithelial surface. Cholesterolα-glucosyltransferase, which is responsible for cholesterol glucosylation in macrophages, was found to contribute to the protection of H. pylori from phagocytosis (Wunder et al, 2006). These lines of evidence suggest that H. pylori can survive intracellularly within specific compartments of macrophages to avoid phagocytosis-mediated killing
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