A pro-inflammatory role for Th22 cells inHelicobacter pylori-associated gastritis

Abstract

ObjectiveHelper T (Th) cell responses are critical for the pathogenesis of Helicobacter pylori-induced gastritis. Th22 cells represent a newly discovered Th cell subset, but their relevance to H. pylori-induced gastritis is unknown.DesignFlow cytometry, real-time PCR and ELISA analyses were performed to examine cell, protein and transcript levels in gastric samples from patients and mice infected with H. pylori. Gastric tissues from interleukin (IL)-22-deficient and wild-type (control) mice were also examined. Tissue inflammation was determined for pro-inflammatory cell infiltration and pro-inflammatory protein production. Gastric epithelial cells and myeloid-derived suppressor cells (MDSC) were isolated, stimulated and/or cultured for Th22 cell function assays.ResultsTh22 cells accumulated in gastric mucosa of both patients and mice infected with H. pylori. Th22 cell polarisation was promoted via the production of IL-23 by dendritic cells (DC) during H. pylori infection, and resulted in increased inflammation within the gastric mucosa. This inflammation was characterised by the CXCR2-dependent influx of MDSCs, whose migration was induced via the IL-22-dependent production of CXCL2 by gastric epithelial cells. Under the influence of IL-22, MDSCs, in turn, produced pro-inflammatory proteins, such as S100A8 and S100A9, and suppressed Th1 cell responses, thereby contributing to the development of H. pylori-associated gastritis.ConclusionsThis study, therefore, identifies a novel regulatory network involving H. pylori, DCs, Th22 cells, gastric epithelial cells and MDSCs, which collectively exert a pro-inflammatory effect within the gastric microenvironment. Efforts to inhibit this Th22-dependent pathway may therefore prove a valuable strategy in the therapy of H. pylori-associated gastritis.

Role of Inflammatory Monocytes in Vaccine-Induced Reduction of Helicobacter felis Infection

“…Moreover, we observed an increased expression of CXCL2 (macrophage inflammatory protein 1␣) during the vaccine-induced reduction of H. felis infection (Fig. 4D); this chemokine has recently been shown to be upregulated in the stomach mucosa of H. pylori-infected patients and responsible for the recruitment of CXCL2R ϩ myeloid suppressive cells in their stomach mucosa (54). We are currently evaluating whether the recruitment of inflammatory monocytes in the vaccine-induced reduction of Helicobacter infection is CXCL2R dependent.…”

Upexpression of BHLHE40 in gastric epithelial cells increases CXCL12 production through interaction with p‐STAT3 in Helicobacter pylori‐associated gastritis

“…The hallmark of H pylori-induced inflammatory response in gastric mucosa is the CD4 + T immune cell's infiltration. 17 Besides, Treg cells also take part in the H pylori-associated gastritis. 18 CD4 + Th cells infiltrating the gastric mucosa could be Th1, Th17, Th22, regulatory T cell (Treg) subsets and so on.…”

“…17 Thus, we stimulated AGS cells with a WT or cagA knockout (ΔcagA) strain of H pylori and found that BHLHE40 mRNA and protein levels only increased following infection with the WT, but not ΔcagA strain ( Figure 3A and Supplementary Figure 4A). cagA is a major virulence factor of H pylori, which is injected into GECs via the type IV secretion system (T4SS).…”

Interleukin-7 Produced by Intestinal Epithelial Cells in Response to Citrobacter rodentium Infection Plays a Major Role in Innate Immunity against This Pathogen

“…Moreover, previous studies have demonstrated that CD4 ϩ LTi cells express IL-22 (28,35), an important cytokine in eliciting an antimicrobial immune response and maintaining mucosal barrier integrity within the intestine (36,37), in an IL-23-dependent manner (28,37). We showed that IL-7R␣ blockade in C. rodentium-infected mice led to a significant decrease in IL-23 expression in the colon, which may in turn inhibit the production of IL-22 by CD4 ϩ LTi cells.…”