title: CCR2 mediates Helicobacter pylori-induced immune tolerance and contributes to mucosal homeostasis.
abstract: BACKGROUND
  We previously demonstrated that H. pylori infection leads to increased induction of regulatory T cells in local and systemic immune compartments. Here, we investigate the role of CCR2 in the tolerogenic programing of dendritic cells in a mouse model of H. pylori infection.
  
  
  METHODS
  CCR2 deficient (CCR2KO) mice and wild-type (Wt) mice infected with H. pylori SS1 strain were analyzed by qPCR and FACS analysis. In vitro, bone marrow-derived DC on day 6 from CCR2KO and Wt mice cocultured with or without H. pylori were examined to determine the impact of CCR2 signaling on dendritic cells function by qPCR, ELISA, and FACS analyses.
  
  
  RESULTS
  Acute H. pylori infection was associated with a threefold increase in CCR2 mRNA expression in the gastric mucosa. H. pylori-infected CCR2KO mice exhibited a higher degree of mucosal inflammation, that is, increased gastritis scores and pro-inflammatory cytokine mRNA levels, but lower degree of H. pylori gastric colonization compared to infected Wt mice. Peripheral H. pylori-specific immune response measured in the CCR2KO spleen was characterized by a higher Th17 response and a lower Treg response. In vitro, CCR2KO bone marrow-derived DC was less mature and shown a lower Treg/Th17 ratio. Moreover, blockade of CCR2 signaling by MCP-1 neutralizing antibody inhibited H. pylori-stimulated bone marrow-derived DC maturation.
  
  
  CONCLUSIONS
  Our results indicate that CCR2 plays an essential role in H. pylori-induced immune tolerance and shed light on a novel mechanism of CCR2-dependent DC Treg induction, which appears to be important in maintaining mucosal homeostasis during H. pylori infection.
authors.affiliation: Department of Pharmacology, School of Medicine, Shandong University, Jinan, Shandong, China.|Department of Internal Medicine, Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Xia
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Mohamad
authors.initials: M
authors.lastname: El-Zaatari
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: Gray B
authors.initials: GB
authors.lastname: Huffnagle
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI, USA.
authors.forename: John Y
authors.initials: JY
authors.lastname: Kao
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D016481:Helicobacter Infections / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology*; D006706:Homeostasis; D007108:Immune Tolerance; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D054390:Receptors, CCR2 / Q000172:deficiency / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2
keywords: Chemokine receptor 2; adaptive immunity; dendritic cells; immature; immune tolerance