A pro-inflammatory role for Th22 cells in Helicobacter pylori-associated gastritis

Objective Helper 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. Design Flow 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. Results Th22 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. Conclusions This 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.

[1]  C. Geczy,et al.  S100 calgranulin proteins S100A8, S100A9 and S100A12 are expressed in the inflamed gastric mucosa of Helicobacter pylori-infected children. , 2008, Canadian journal of gastroenterology = Journal canadien de gastroenterologie.

[2]  John Bertin,et al.  Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island , 2004, Nature Immunology.

[3]  J. Sirard,et al.  Interleukin-22 Reduces Lung Inflammation during Influenza A Virus Infection and Protects against Secondary Bacterial Infection , 2013, Journal of Virology.

[4]  C. O'Morain,et al.  Helicobacter pylori Infection , 1994 .

[5]  C. Loddenkemper,et al.  Interleukin (IL)-23 mediates Toxoplasma gondii–induced immunopathology in the gut via matrixmetalloproteinase-2 and IL-22 but independent of IL-17 , 2009, The Journal of experimental medicine.

[6]  B. Jenkins,et al.  Nucleotide Oligomerization Domain 1 Enhances IFN-γ Signaling in Gastric Epithelial Cells during Helicobacter pylori Infection and Exacerbates Disease Severity , 2013, The Journal of Immunology.

[7]  B. Roe,et al.  Analyses of the cag pathogenicity island of Helicobacter pylori , 1998, Molecular microbiology.

[8]  A. Takayanagi,et al.  Interleukin-22, a member of the IL-10 subfamily, induces inflammatory responses in colonic subepithelial myofibroblasts. , 2005, Gastroenterology.

[9]  A. A. Akhiani,et al.  Protection Against Helicobacter pylori Infection Following Immunization Is IL-12-Dependent and Mediated by Th1 Cells1 , 2002, The Journal of Immunology.

[10]  D. Philpott,et al.  NF-kappaB activation during acute Helicobacter pylori infection in mice. , 2008, Infection and immunity.

[11]  D. Foell,et al.  Proinflammatory S100 Proteins Regulate the Accumulation of Myeloid-Derived Suppressor Cells1 , 2008, The Journal of Immunology.

[12]  F. Powrie,et al.  Innate lymphoid cells sustain colon cancer through production of interleukin-22 in a mouse model , 2013, The Journal of experimental medicine.

[13]  M. J. Broadhurst,et al.  IL-22+ CD4+ T Cells Are Associated with Therapeutic Trichuris trichiura Infection in an Ulcerative Colitis Patient , 2010, Science Translational Medicine.

[14]  R. D. Hatton,et al.  Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. , 2012, Immunity.

[15]  E. Artifon,et al.  Competing interests: None , 2016 .

[16]  Ruth R. Montgomery,et al.  IL-22 Signaling Contributes to West Nile Encephalitis Pathogenesis , 2012, PloS one.

[17]  M. Cobleigh,et al.  A proinflammatory role for interleukin-22 in the immune response to hepatitis B virus. , 2011, Gastroenterology.

[18]  C. McCall,et al.  Myeloid-Derived Suppressor Cells Evolve during Sepsis and Can Enhance or Attenuate the Systemic Inflammatory Response , 2012, Infection and Immunity.

[19]  H. Rautelin,et al.  Persisting Chronic Gastritis and Elevated Helicobacter pylori Antibodies after Successful Eradication Therapy , 2007, Helicobacter.

[20]  C. Geczy,et al.  S 100 calgranulin proteins S 100 A 8 , S 100 A 9 and S 100 A 12 are expressed in the inflamed gastric mucosa of Helicobacter pylori-infected children , 2016 .

[21]  Srinivas Nagaraj,et al.  Myeloid-derived suppressor cells as regulators of the immune system , 2009, Nature Reviews Immunology.

[22]  Nathalie Arbour,et al.  Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation , 2007, Nature Medicine.

[23]  J. Carucci,et al.  Human Langerhans cells induce distinct IL-22-producing CD4+ T cells lacking IL-17 production , 2009, Proceedings of the National Academy of Sciences.

[24]  R. Sun,et al.  Interleukin 22 (IL‐22) plays a protective role in T cell‐mediated murine hepatitis: IL‐22 is a survival factor for hepatocytes via STAT3 activation , 2004, Hepatology.

[25]  S. Wong,et al.  Increased Myeloid-Derived Suppressor Cells in Gastric Cancer Correlate with Cancer Stage and Plasma S100A8/A9 Proinflammatory Proteins , 2013, The Journal of Immunology.

[26]  F. Hu,et al.  Expansion of Monocytic Myeloid-Derived Suppressor Cells Dampens T Cell Function in HIV-1-Seropositive Individuals , 2012, Journal of Virology.

[27]  A. Murphy,et al.  Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. , 2008, Immunity.

[28]  Ken B. Waites,et al.  Helicobacter pylori-Induced Mucosal Inflammation Is Th1 Mediated and Exacerbated in IL-4, But Not IFN-γ, Gene-Deficient Mice1 , 2000, The Journal of Immunology.

[29]  C. Weaver,et al.  The β-Glucan Receptor Dectin-1 Promotes Lung Immunopathology during Fungal Allergy via IL-22 , 2012, The Journal of Immunology.

[30]  D. Philpott,et al.  NF-κB Activation during Acute Helicobacter pylori Infection in Mice , 2007, Infection and Immunity.

[31]  Mark J. Miller,et al.  Helicobacter pylori immune escape is mediated by dendritic cell-induced Treg skewing and Th17 suppression in mice. , 2010, Gastroenterology.

[32]  H. Luhmann,et al.  An alternative pathway of imiquimod-induced psoriasis-like skin inflammation in the absence of interleukin-17 receptor a signaling. , 2013, The Journal of investigative dermatology.

[33]  D. Philpott,et al.  Reduced activation of inflammatory responses in host cells by mouse‐adapted Helicobacter pylori isolates , 2002, Cellular microbiology.

[34]  P. Valdez,et al.  Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis , 2007, Nature.