Original ResearchBasic and Translational—Alimentary TractGastric Sonic Hedgehog Acts as a Macrophage Chemoattractant During the Immune Response to Helicobacter pylori
Section snippets
Animal Models
A mouse model expressing a parietal cell–specific deletion of Shh (formerly known as HKCre/ShhKO, referred to as PC-ShhKO in the current studies) was generated as previously reported.14 Age-matched Shh loxP (homozygous for the loxP sites without the Cre transgene) and HKCre littermates were used as controls.
PC-ShhKO mice were crossed with gastrin-deficient mice (GKO) to generate double-knockout PC-ShhKO/GastrinKO mice. Gastrin deficiency was confirmed by radioimmunoassay and polymerase chain
H pylori–Infected PC-ShhKO Mice Fail to Develop Gastritis
To determine the role of gastric Shh signaling in the initiation of gastritis, control and PC-ShhKO mice were infected with H pylori and analyzed 6 months after inoculation. Histologic examination revealed that H pylori generated a significant inflammatory response in the control group (Figure 1B) compared with the uninfected animals (Figure 1A). Interestingly, PC-ShhKO mice did not develop an inflammatory response after 6 months of H pylori infection (Figure 1C and D). The characteristic
Discussion
Hedgehog signaling components Ptch, Smo, and Gli are all expressed in macrophages.19, 23 Furthermore, pathway analysis of lipopolysaccharide-stimulated macrophages revealed that Hedgehog signaling genes were up-regulated within 24 hours, showing a capacity for stimulated macrophages to be Hedgehog responsive.34 Bone marrow chimera experiments using LysMCre/SmoKO mice showed the role of gastric Shh as a macrophage chemoattractant. First, the targeted deletion of Hedgehog signaling within the
Acknowledgments
The authors thank Dr Marsha Wills–Karp and Alyssa Sproles of the Cincinnati Cytokine/Chemokine/Mediator Measurement Core at the Digestive Health Center of Cincinnati Children's Medical Health Center for assistance and Dr Kathryn A. Eaton (Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI) for her discussion and suggestions.
References (42)
- et al.
A predominant Th1 type of immune response is induced early during acute Helicobacter pylori infection in rhesus macaques
Gastroenterology
(2000) - et al.
The inflammatory and immune response to Helicobacter pylori infection
Best Pract Res Clin Gastroenterol
(2007) - et al.
Immunology of Helicobacter pylori: insights into the failure of the immune response and perspectives on vaccine studies
Gastroenterology
(2007) - et al.
Helicobacter pylori induces ERK-dependent formation of a phospho-c-Fos c-Jun activator protein-1 complex that causes apoptosis in macrophages
J Biol Chem
(2010) - et al.
Commercially available recombinant Sonic Hedgehog up-regulates Ptc and modulates the cytokine and chemokine expression of human macrophages: an effect mediated by endotoxin contamination?
Immunobiology
(2008) - et al.
Hh pathway expression in human gut tissues and in inflammatory gut diseases
Lab Invest
(2004) - et al.
A standardized mouse model of Helicobacter pylori infection: introducing the Sydney strain
Gastroenterology
(1997) - et al.
Genetic or chemical hypochlorhydria is associated with inflammation that modulates parietal and G-cell populations in mice
Gastroenterology
(2002) - et al.
Cyclopamine inhibition of the Sonic Hedgehog pathway in the stomach requires concomitant acid inhibition
Regul Pept
(2008) - et al.
Reduced pepsin A processing of Sonic Hedgehog in parietal cells precedes gastric atrophy and transformation
J Biol Chem
(2007)
Transfer of differentiation signal by membrane microvesicles harboring hedgehog morphogens
Blood
Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration
Lancet
The role of T cell subsets and cytokines in the pathogenesis of Helicobacter pylori gastritis in mice
J Immunol
Chronic gastritis in the hypochlorhydric gastrin-deficient mouse progresses to adenocarcinoma
Oncogene
Treatment of Helicobacter gastritis with IL-4 requires somatostatin
Proc Natl Acad Sci U S A
Host response to Helicobacter pylori infection before initiation of the adaptive immune response
FEMS Immunol Med Microbiol
NF-kappaB activation during acute Helicobacter pylori infection in mice
Infect Immun
Role of NF-kappaB and AP-1 on Helicobater pylori-induced IL-8 expression in AGS cells
Dig Dis Sci
Monocyte chemoattractant protein-1 is generated via TGF-beta by myofibroblasts in gastric intestinal metaplasia and carcinoma without H. pylori infection
Cancer Sci
Role of neutrophils in a rat model of gastric ulcer recurrence caused by interleukin-1 beta
Am J Pathol
Macrophages are mediators of gastritis in acute Helicobacter pylori infection in C57BL/6 mice
Infect Immun
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by National Institutes of Health grant 1R01DK083402-01 (to Y.Z.) and in part by the Digestive Health Center of Cincinnati Children's Medical Health Center (DHC: Bench to Bedside Research in Pediatric Digestive Disease) grant CHTF/SUB DK078392. Monica DeLay, manager of the Research Flow Cytometry Core in the Division of Rheumatology at Cincinnati Children's Hospital Medical Center, provided assistance and was supported in part by National Institutes of Health grant AR-47363. All flow cytometric data were acquired using equipment maintained by the Research Flow Cytometry Core in the Division of Rheumatology at Cincinnati Children's Hospital Medical Center, which was supported in part by National Institutes of Health grant AR-47363.