Berberine regulates macrophage polarization through IL-4-STAT6 signaling pathway in Helicobacter pylori-induced chronic atrophic gastritis

Abstract

Aims: We will investigate the anti-inflammatory activities of berberine (BBR) in treating chronic atrophic gastritis (CAG) induced by Helicobacter pylori (H. pylori). Furthermore, the underlying molecular mechanisms of BBR also will be explored systematically.

Materials and methods: Rats were infected by H. pylori. Lipopolysaccharide (LPS) and H. pylori were applied to induce M1 Mφs polarization, interleukin 4 (IL-4) and BBR were used to induce M2 Mφs polarization. Supernatants of polarized Mφs were collected as conditioned media (CM) for investigating the impact of Mφs and its' secreted cytokine on gastric epithelial cells (GES-1). Cell viability, morphology, proliferation, and quantitative analysis of RAW 264.7 cells and GES-1 cells were detected by high-content screening (HCS) imaging assay. To further investigate the potential mechanisms of BBR, relative mRNA, immunohistochemistry and protein expression were measured.

Key findings: BBR inhibited M1-polarized Mφs, which was induced by H. pylori and LPS, and advocated M2-polarized Mφs. The M1-specific markers (TNF-α and IFN-γ) in supernatants were reduced significantly and M2 specific markers (TGF-β and IL-10) were increased obviously under BBR intervention. In addition, BBR significantly protected GES-1 from M1-polarized Mφs injury. The mRNA expression of M1-polarized Mφs, including TNF-α, NOS2, CCR7, and IRF-8, were suppressed by BBR administration and the mRNA expression of M2-polarized Mφs, including IL-4, STAT6, IL-10 and Chil3, were increased by BBR intervention. Meanwhile, BBR activated IL-4-STAT6 signaling pathway in vivo and in vitro when H. pylori infection and presented anti-inflammatory activities.

Significance: BBR promotes M2-polarized Mφs when H. pylori infection. The anti-inflammatory properties of BBR tightly related to M1-polarized Mφs inhibition and M2-polarized Mφs promotion. BBR activates IL-4-STAT6 signaling pathway, which is crucial exceedingly in M2 Mφs activation and anti-inflammatory response.

Keywords: Berberine; Chronic atrophic gastritis; Helicobacter pylori; Macrophages.