Schlafen 4-expressing myeloid-derived suppressor cells are induced during murine gastric metaplasia

Lin Ding, Michael M. Hayes, Amanda Photenhauer, Kathryn A. Eaton, Qian Li, Ramon Ocadiz-Ruiz, Juanita L. Merchant

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

Chronic Helicobacter pylori infection triggers neoplastic transformation of the gastric mucosa in a small subset of patients, but the risk factors that induce progression to gastric metaplasia have not been identified. Prior to cancer development, the oxyntic gastric glands atrophy and are replaced by metaplastic cells in response to chronic gastritis. Previously, we identified schlafen 4 (Slfn4) as a GLI1 target gene and myeloid differentiation factor that correlates with spasmolytic polypeptide-expressing metaplasia (SPEM) in mice. Here, we tested the hypothesis that migration of SLFN4-expressing cells from the bone marrow to peripheral organs predicts preneoplastic changes in the gastric microenvironment. Lineage tracing in Helicobacter-infected Slfn4 reporter mice revealed that SLFN4+ cells migrated to the stomach, where they exhibited myeloid-derived suppressor cell (MDSC) markers and acquired the ability to inhibit T cell proliferation. SLFN4+ MDSCs were not observed in infected GLI1-deficient mice. Overexpression of sonic hedgehog ligand (SHH) in infected WT mice accelerated the appearance of SLFN4+ MDSCs in the gastric corpus. Similarly, in the stomachs of H. pylori-infected patients, the human SLFN4 ortholog SLFN12L colocalized to cells that expressed MDSC surface markers CD15+CD33+HLADRlo. Together, these results indicate that SLFN4 marks a GLI1-dependent population of MDSCs that predict a shift in the gastric mucosa to a metaplastic phenotype.

Original languageEnglish (US)
Pages (from-to)2867-2880
Number of pages14
JournalJournal of Clinical Investigation
Volume126
Issue number8
DOIs
StatePublished - Aug 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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