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

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

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+HLA-DRlo. 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.

Authors

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

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Figure 5

Analysis of DAMP signaling components in H. felis–infected corpus.

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Analysis of DAMP signaling components in H. felis–infected corpus. Total...
Total RNA was extracted from H. felis–infected WT and pCMV-Shh corpus lysates and analyzed by RT-qPCR for (A) Tlr9, (B) Myd88, (C) Ifnb1, (D) Irf7, and (E) Ifna mRNA at the indicated time points, and then expressed as fold change relative to uninfected WT mice (UI). (F) Serum IFN-α levels determined by ELISA. Shown are the median and interquartile range for n = 8–10 mice per group over 3 experiments. One-way ANOVA followed by Tukey’s multiple comparisons test on log-transformed values was performed. *P < 0.05, **P < 0.01, ‡P < 0.001. Immunofluorescence images for (G) IFN-β1 and (H) cleaved caspase-3 with H+-K+-ATPase (HK-ATPase) in the gastric corpus of 2-month H. felis–infected pCMV-Shh mice. Inset: Image of uninfected pCMV-Shh gastric corpus stained for cleaved caspase-3. Asterisks and arrows indicate nonapoptotic and apoptotic cells, respectively. G: left, original magnification, ×200; G, right, and H: magnification, ×400); (I) Images for IFN-α with E-cadherin in 4-month-infected pCMV-Shh mice. I, left: original magnification, ×200; I, right: magnification, ×600. White boxes indicate enlarged regions. Images in G–I are representative of n = 3 mouse stomachs.