Helicobacter pylori-induced adrenomedullin modulates IFN-\u03b3-producing T-cell responses and contributes to gastritis

Hui Kong,Han Chen,Yuan Zhuang,Yi-Pin Lv,Yu-Gang Liu,Nan You,Yong-Sheng Teng,Gang Guo,Quan-Ming Zou,Weisan Chen,Jin-Yu Zhang,Zhuo Zhao,Fang-Yuan Mao,Ping Cheng

doi:10.1038/s41419-020-2391-6

Abstract

Adrenomedullin (ADM) is a multifunctional peptide that is expressed by many surface epithelial cells, but its relevance to Helicobacter pylori (H. pylori)-induced gastritis is unknown. Here, we found that gastric ADM expression was elevated in gastric mucosa of H. pylori-infected patients and mice. In H. pylori-infected human gastric mucosa, ADM expression was positively correlated with the degree of gastritis; accordingly, blockade of ADM resulted in decreased inflammation within the gastric mucosa of H. pylori-infected mice. During H. pylori infection, ADM production was promoted via PI3K–AKT signaling pathway activation by gastric epithelial cells in a cagA-dependent manner, and resulted in increased inflammation within the gastric mucosa. This inflammation was characterized by the increased IFN-γ-producing T cells, whose differentiation was induced via the phosphorylation of AKT and STAT3 by ADM derived from gastric epithelial cells. ADM also induced macrophages to produce IL-12, which promoted the IFN-γ-producing T-cell responses, thereby contributing to the development of H. pylori-associated gastritis. Accordingly, blockade of IFN-γ or knockout of IFN-γ decreased inflammation within the gastric mucosa of H. pylori-infected mice. This study identifies a novel regulatory network involving H. pylori, gastric epithelial cells, ADM, macrophages, T cells, and IFN-γ, which collectively exert a pro-inflammatory effect within the gastric microenvironment.

Highlights

Helicobacter pylori (H. pylori) is a Gram-negative bacterium that infects more than half of the world’s population[1]
H. pylori infection is a threat to human health, for example, the long-term colonization of H. pylori in the stomach can change the pH of the stomach, promoting chronic gastritis, gastric ulcers, and even gastric cancer[2]
Until now, the mechanism of H. pylori-associated chronic gastritis remains unclear, and it is believed that the interplays between host and bacterial virulence factors[21,27], such as vacA15,28,29, especially a major virulence factor cagA that can be injected into the host cell by Type IV Secretion System (T4SS)[30], and that will be phosphorylated after entering the host gastric epithelial cells[31], and the following persistent inflammation, are likely the underlying causes

Summary

Introduction

Helicobacter pylori (H. pylori) is a Gram-negative bacterium that infects more than half of the world’s population[1]. H. pylori is an important factor of chronic gastritis, peptic ulcer, and other digestive system diseases, and has been classified as a class I carcinogen by WHO2. Gastric epithelial cells produce a variety of cytokines that are involved in the inflammatory. Many immune cells, such as neutrophils, lymphocytes, and plasma cells, are releasing inflammatory factors in the stomach of H. pylori infection[4,5,6]. Inflammatory reaction to H. pylori infection shows special characteristics rarely seen in other organs or biological systems, and the mixed acute and chronic inflammatory reactions contribute to H. pylori-associated gastritis, and take place simultaneously during H. pylori infection[7,8,9]. Adrenomedullin (ADM) is a small active hormone that is expressed throughout the gastrointestinal tract[10]. ADM that consists of 52 amino acids is structurally similar to calcitonin gene-related peptide, dextrin, and pituitary[11]

Methods

Results

Conclusion