Gastric sonic hedgehog acts as a macrophage chemoattractant during the immune response to Helicobacter pylori

Michael A. Schumacher; Jessica M. Donnelly; Amy C. Engevik; Chang Xiao; Li Yang; Susan Kenny; Andrea Varro; Frédéric Hollande; Linda C. Samuelson; Yana Zavros

doi:10.1053/j.gastro.2012.01.029

Gastric sonic hedgehog acts as a macrophage chemoattractant during the immune response to Helicobacter pylori

Michael A. Schumacher, Jessica M. Donnelly, Amy C. Engevik, Chang Xiao, Li Yang, Susan Kenny, Andrea Varro, Frédéric Hollande, Linda C. Samuelson, Yana Zavros

Research output: Contribution to journal › Article › peer-review

87 Scopus citations

Abstract

Background & Aims: 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.

Original language	English (US)
Pages (from-to)	1150-1159.e6
Journal	Gastroenterology
Volume	142
Issue number	5
DOIs	https://doi.org/10.1053/j.gastro.2012.01.029
State	Published - May 2012
Externally published	Yes

Keywords

Bacteria
Gastric Cancer
Monocyte
Signaling

ASJC Scopus subject areas

Hepatology
Gastroenterology

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10.1053/j.gastro.2012.01.029

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@article{7c9640e0afb34a01a0e31c0641e2de64,

title = "Gastric sonic hedgehog acts as a macrophage chemoattractant during the immune response to Helicobacter pylori",

abstract = "Background & Aims: 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-ShhKO) 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/SmoKO). 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-ShhKO 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/SmoKO mice. Conclusions: H pylori induces release of Shh from the stomach; Shh acts as a macrophage chemoattractant during initiation of gastritis.",

keywords = "Bacteria, Gastric Cancer, Monocyte, Signaling",

author = "Schumacher, {Michael A.} and Donnelly, {Jessica M.} and Engevik, {Amy C.} and Chang Xiao and Li Yang and Susan Kenny and Andrea Varro and Fr{\'e}d{\'e}ric Hollande and Samuelson, {Linda C.} and Yana Zavros",

note = "Funding Information: 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 . ",

year = "2012",

month = may,

doi = "10.1053/j.gastro.2012.01.029",

language = "English (US)",

volume = "142",

pages = "1150--1159.e6",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "5",

}

TY - JOUR

T1 - Gastric sonic hedgehog acts as a macrophage chemoattractant during the immune response to Helicobacter pylori

AU - Schumacher, Michael A.

AU - Donnelly, Jessica M.

AU - Engevik, Amy C.

AU - Xiao, Chang

AU - Yang, Li

AU - Kenny, Susan

AU - Varro, Andrea

AU - Hollande, Frédéric

AU - Samuelson, Linda C.

AU - Zavros, Yana

N1 - Funding Information: 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 .

PY - 2012/5

Y1 - 2012/5

N2 - Background & Aims: 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-ShhKO) 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/SmoKO). 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-ShhKO 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/SmoKO mice. Conclusions: H pylori induces release of Shh from the stomach; Shh acts as a macrophage chemoattractant during initiation of gastritis.

AB - Background & Aims: 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-ShhKO) 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/SmoKO). 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-ShhKO 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/SmoKO mice. Conclusions: H pylori induces release of Shh from the stomach; Shh acts as a macrophage chemoattractant during initiation of gastritis.

KW - Bacteria

KW - Gastric Cancer

KW - Monocyte

KW - Signaling

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JO - Gastroenterology

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Gastric sonic hedgehog acts as a macrophage chemoattractant during the immune response to Helicobacter pylori

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