title: Gastric Sonic Hedgehog acts as a macrophage chemoattractant during the immune response to Helicobacter pylori.
abstract: OBJECTIVE
  Macrophages mediate the epithelial response to Helicobacter pylori and are involved in the development of gastritis. Sonic Hedgehog (Shh) regulates gastric epithelial differentiation and function, but little is known about its immunoregulatory role in the stomach. We investigated whether gastric Shh acts as a macrophage chemoattractant during the innate immune response to H pylori infection.
  
  
  METHODS
  Mice with parietal cell-specific deletion of Shh (PC-Shh(KO)) and control mice were infected with H pylori. Levels of gastric Shh, cytokines, and chemokines were assayed by quantitative reverse-transcriptase polymerase chain reaction or by a Luminex-based multiplex assay 2, 7, or 180 days after infection. Circulating concentrations of Shh were measured by enzyme-linked immunosorbent assay. Bone marrow chimera experiments were performed with mice that have myeloid cell-specific deletion of the Hedgehog signal transduction protein Smoothened (LysMCre/Smo(KO)). Macrophage recruitment was measured in gastric tissue and peripheral blood by fluorescence-activated cell sorting analysis.
  
  
  RESULTS
  Control mice infected with H pylori for 6 months developed an inflammatory response characterized by infiltration of CD4(+) T cells and increased levels of interferon gamma and interleukin 1β in the stomach. PC-Shh(KO) mice did not develop gastritis, even after 6 months of infection with H pylori. Control mice had increased concentrations of Shh, accompanied by the recruitment of CD11b(+)F4/80(+)Ly6C(high) macrophages 2 days after infection. Control mice that received bone marrow transplants from control mice had an influx of macrophages to the gastric mucosa in response to H pylori infection; this was not observed in H pylori-infected control mice that received bone marrow transplants from LysMCre/Smo(KO) mice.
  
  
  CONCLUSIONS
  H pylori induces release of Shh from the stomach; Shh acts as a macrophage chemoattractant during initiation of gastritis.
authors.affiliation: Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0576, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Schumacher
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Donnelly
authors.forename: Amy C
authors.initials: AC
authors.lastname: Engevik
authors.forename: Chang
authors.initials: C
authors.lastname: Xiao
authors.forename: Li
authors.initials: L
authors.lastname: Yang
authors.forename: Susan
authors.initials: S
authors.lastname: Kenny
authors.forename: Andrea
authors.initials: A
authors.lastname: Varro
authors.forename: Frédéric
authors.initials: F
authors.lastname: Hollande
authors.forename: Linda C
authors.initials: LC
authors.lastname: Samuelson
authors.forename: Yana
authors.initials: Y
authors.lastname: Zavros
mesh_terms: D000818:Animals; D002630:Chemotactic Factors / Q000502:physiology*; D005756:Gastritis / Q000209:etiology; D053823:Hedgehog Proteins / Q000097:blood / Q000502:physiology*; D016481:Helicobacter Infections / Q000150:complications / Q000276:immunology*; D016480:Helicobacter pylori / Q000276:immunology*; D018664:Interleukin-12 / Q000502:physiology; D053583:Interleukin-1beta / Q000502:physiology; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D015398:Signal Transduction; D013270:Stomach / Q000276:immunology*
chemical_list: D002630:Chemotactic Factors; D053823:Hedgehog Proteins; D053583:Interleukin-1beta; C465570:Shh protein, mouse; D018664:Interleukin-12