Helicobacter pylori-induced REDD1 modulates Th17 cell responses that contribute to gastritis

Abstract

Objective: Regulated in development and DNA damage responses-1 (REDD1) is a conserved and ubiquitous protein, which is induced in response to multiple stimuli. However, the regulation, function and clinical relevance of REDD1 in Helicobacter pylori-associated gastritis are presently unknown. Approach: Immunohistochemistry, real-time PCR and Western blot analyses were performed to examine the levels of REDD1 in gastric samples from H. pylori-infected patients and mice. Gastric tissues from Redd1−/− and wildtype (WT, control) mice were examined for inflammation. Gastric epithelial cells (GECs), monocytes and T cells were isolated, stimulated and/or cultured for REDD1 regulation and functional assays. Results: REDD1 was increased in gastric mucosa of H. pylori-infected patients and mice. H. pylori induced GECs to express REDD1 via the phosphorylated cytotoxin associated gene A (cagA) that activated MAPKp38 pathway to mediate NF-κB directly binding to REDD1 promoter. Human gastric REDD1 increased with the severity of gastritis, and mouse REDD1 from non-marrow chimera-derived cells promoted gastric inflammation that was characterized by the influx of MHCII+ monocytes. Importantly, gastric inflammation, MHCII+ monocyte infiltration, IL-23 and IL-17A were attenuated in Redd1−/− mice. Mechanistically, REDD1 in GECs regulated CXCL1 production, which attracted MHCII+ monocytes migration by CXCL1-CXCR2 axis. Then H. pylori induced MHCII+ monocytes to secrete IL-23, which favored IL-17A-producing CD4+ cell (Th17 cell) polarization, thereby contributing to the development of H. pylori-associated gastritis. Conclusions: The present study identifies a novel regulatory network involving REDD1, which collectively exert a pro-inflammatory effect within gastric microenvironment. Efforts to inhibit this REDD1-dependent pathway may prove valuable strategies in treating of H. pylori-associated gastritis.

Effect of Probiotic-Assisted Eradication of cagA+/vacA s1m1 Helicobacter pylori on Intestinal Flora

“…There were remarkable associations between serum TNF-α and IL-8 levels and the degree of mucosa chronic inflammation in patients [37]. The Th17/ IL-17 immunoregulatory pathway is involved in H. pylori colonization and immune-inflammatory response [38]. The expression level of IL-17 was markedly elevated in the of H. pylori-infected individuals.…”

Strategies of Helicobacter pylori in evading host innate and adaptive immunity: insights and prospects for therapeutic targeting

“…Mouse model studies have further revealed that this action of cagA intensifies gastritis progression in non-bone marrow-derived cells. Furthermore, cagA increases the expression of CXCL1, promoting the migration of MHC II+ mononuclear cells and the secretion of IL-23, which collectively lead to Th17 cell polarization and IL-17A production, exacerbating inflammation induced by H. pylori ( Yan et al., 2021 ). These findings deepen our understanding of cagA and its associated pathogenicity island (cagPAI) in the immune response elicited by H. pylori .…”

Treatment of Chronic Gastritis with Traditional Chinese Medicine: Pharmacological Activities and Mechanisms

“…The main reasons are heredity, constitution, immunity, diet and environment, Hp infection in the digestive tract, long-term use of drugs that stimulate the stomach (non-steroidal anti-inflammatory drugs, alcohol, etc.) and so on [ 20 , 21 , 22 , 23 ]. At present, it is found that Hp infection, diet, and environmental factors are the key factors that induce chronic gastritis.…”