4.7 Article

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

期刊

CLINICAL SCIENCE
卷 135, 期 22, 页码 2541-2558

出版社

PORTLAND PRESS LTD
DOI: 10.1042/CS20210753

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资金

  1. National Natural Science Foundation of China [82070578, 82000530, 81773042, 81670510]
  2. Chongqing Natural Science Fund for Distinguished Young Scholars [cstc2019jcyjjqX0003]
  3. Sci-ence Innovation Capacity Promotion Project of Army Medical University [2019XQY03]
  4. Innovation Research Group in Colleges and Universities Program of Chongqing Municipal Education Commission [CXQT20012]

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The study found that REDD1 is increased in the gastric mucosa of H. pylori-infected patients and mice. H. pylori induced GECs to express REDD1 via the phosphorylated cagA, activating the MAPKp38 pathway. In Redd1-/- mice, gastric inflammation, MHCII+ monocyte infiltration, IL-23, and IL-17A were all attenuated.
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-Kappa B 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.

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