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Gli1 deletion prevents Helicobacter-induced gastric metaplasia and expansion of myeloid cell subsets.

ABSTRACT: Chronic inflammation in the stomach induces metaplasia, the pre-cancerous lesion that precedes inflammation-driven neoplastic transformation. While Hedgehog signaling contributes to the initiation of some cancers, its role in gastric transformation remains poorly defined. We found that Helicobacter-infected C57BL/6 mice develop extensive mucous cell metaplasia at 6 month but not at 2 months post-infection. Gastric metaplasia coincided with the appearance of CD45(+)MHCII(+)CD11b(+)CD11c(+) myeloid cells that were normally not present in the chronic gastritis at 2 months. The myeloid regulatory gene Schlafen-4 was identified in a microarray analysis comparing infected WT versus Gli1 null mice and was expressed in the CD11b(+)CD11c(+) myeloid population. Moreover this same population expressed IL-1? and TNF? pro-inflammatory cytokines. By 6 months, the mucous neck cell metaplasia (SPEM) expressed IL-6, phosphorylated STAT3 and the proliferative marker Ki67. Expression was not observed in Gli1 mutant mice consistent with the requirement of Gli1 to induce this pre-neoplastic phenotype. Ectopic Shh ligand expression alone was not sufficient to induce SPEM, but with Helicobacter infection synergistically increased the histologic severity observed with the inflammation. Therefore Hedgehog signaling is required, but is not sufficient to generate pre-neoplastic changes during chronic gastritis. Gli1-dependent myeloid cell differentiation plays a pivotal role in the appearance of myeloid cell subtypes ostensibly required for SPEM development. Moreover, it suggests that therapies capable of targeting this phenotypic switch might prevent progression to metaplasia, the pre-neoplastic change that develops prior to dysplasia and gastric cancer, which also occurs in other epithelial-derived neoplasias initiated by chronic inflammation.

SUBMITTER: El-Zaatari M

PROVIDER: S-EPMC3592845 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Gli1 deletion prevents Helicobacter-induced gastric metaplasia and expansion of myeloid cell subsets.

El-Zaatari Mohamad M Kao John Y JY Tessier Art A Bai Longchuan L Hayes Michael M MM Fontaine Clinton C Eaton Kathryn A KA Merchant Juanita L JL

PloS one 20130308 3

Chronic inflammation in the stomach induces metaplasia, the pre-cancerous lesion that precedes inflammation-driven neoplastic transformation. While Hedgehog signaling contributes to the initiation of some cancers, its role in gastric transformation remains poorly defined. We found that Helicobacter-infected C57BL/6 mice develop extensive mucous cell metaplasia at 6 month but not at 2 months post-infection. Gastric metaplasia coincided with the appearance of CD45(+)MHCII(+)CD11b(+)CD11c(+) myeloi ...[more]

PMID: 23520544

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Project description:IntroductionMDSCs express SCHLAFEN 4 (SLFN4) in Helicobacter-infected stomachs coincident with spasmolytic polypeptide-expressing metaplasia (SPEM), a precursor of gastric cancer. We aimed to characterize SLFN4+ cell identity and the role of Slfn4 in these cells.MethodsSingle-cell RNA sequencing was performed on immune cells sorted from PBMCs and stomachs prepared from uninfected and 6-month H. felis-infected mice. Knockdown of Slfn4 by siRNA or PDE5/6 inhibition by sildenafil were performed in vitro. Intracellular ATP/GTP levels and GTPase activity of immunoprecipitated Slfn4 complexes were measured using the GTPase-Glo assay kit. The intracellular level of ROS was quantified by the DCF-DA fluorescent staining, and apoptosis was determined by cleaved Caspase-3 and Annexin V expression. Gli1CreERT2 x Slfn4 fl/fl mice were generated and infected with H. felis. Sildenafil was administered twice over 2 weeks by gavaging H. felis infected mice ~4 months after inoculation once SPEM had developed.ResultsSlfn4 was highly induced in both monocytic and granulocytic MDSCs from infected stomachs. Both Slfn4 +-MDSC populations exhibited strong transcriptional signatures for type-I interferon responsive GTPases and exhibited T cell suppressor function. SLFN4-containing protein complexes immunoprecipitated from myeloid cell cultures treated with IFNa exhibited GTPase activity. Knocking down Slfn4 or PDE5/6 inhibition with sildenafil blocked IFNa induction of GTP, SLFN4 and NOS2. Moreover, IFNa induction of Slfn +-MDSC function was inhibited by inducing their reactive oxygen species (ROS) production and apoptosis through protein kinase G activation. Accordingly, in vivo disruption of Slfn4 in Gli1CreERT2 x Slfn4 fl/fl mice or pharmacologic inhibition by sildenafil after Helicobacter infection also suppressed SLFN4 and NOS2, reversed T cell suppression and mitigated SPEM development.ConclusionTaken together, SLFN4 regulates the activity of the GTPase pathway in MDSCs and precludes these cells from succumbing to the massive ROS generation when they acquire MDSC function.

Project description:The objectives of this study were to investigate the serum pepsinogen test for the prediction of OLGIM (Operative Link on Gastric Intestinal Metaplasia Assessment) stages in first-degree relatives (FDR-GC) of patients with gastric cancer (GC) and autoimmune chronic atrophic gastritis (ACAG).In 67 consecutive patients with ACAG, 82 FDR-GC, and 53 controls (CTRL) without gastric disease (confirmed by biopsy), serum levels of pepsinogen 1 (PG1), pepsinogen 2 (PG2), G17, and the PG1/2 ratio were assessed by enzyme-linked immunosorbent assay kit. All ACAG patients had positive antiparietal cell antibody levels, estimated by indirect immunofluorescence. Biopsies taken in duplicate from the antrum, corpus, and fundus were stained with Giemsa for Helicobacter pylori detection. Endoscopic detection of metaplasia was confirmed by histological diagnosis. Histological classification of OLGIM stages was applied by using the criteria of severity and topography of intestinal metaplasia (IM).The highest discrimination capacity for distinguishing ACAG from other groups of patients was the gastrin G17 test. The lowest mean for PG1 and PG2 serum levels was found in ACAG. In multivariate analysis by age, PG1 and PG1/PG2 were independent prognostic factors for metaplasia, and PG2 also for the presence of a histological H. pylori infection. The serum PG1 level was significantly lower in individuals with IM at OLGIM stage >2 than in those with IM at OLGIM stage <2, resulting in a useful method for the prediction of OLGIM stage. With the inclusion of patient age at diagnosis in the prediction of ≥2 vs. 0-1 OLGIM stages, the receiver operating characteristic (ROC) curve at 47.9 ng/ml PG1 level reached a significant area under the curve (AUC) value (0.978, P<0.001). We also observed a slight difference in PG2 serum levels between histological H. pylori-positive and H. pylori-negative subjects (ROC AUC: 0.599).This study demonstrated an important increase in gastrin G17 serum level in autoimmune gastritis. PG1 serum level corrected by patient age can be used in the management of patients at risk for GC with a high predicted probability of having an OLGIM stage ≥2. Using a cutoff of 47.9 ng/ml, PG1 testing in FDR-GC and ACAG patients had a sensitivity of 95.83% and a specificity of 93.37. Although these results could be validated in a prospective study, the known importance of higher OLGIM stages in increasing the risk of GC development supports the rationale of proposing PG1 algorithm as a diagnostic tool for the selection of high-risk FDR-GC and ACAG patients at high-risk stages for subsequent detailed endoscopic examination to detect dysplasia and asymptomatic GC. In addition, serum PG1 and PG2 levels could stratify patients based on both H. pylori infection and OLGIM risk in consideration of the increased acknowledge regarding the role of H. pylori in the progression of gastritis to GC.

Dataset Information

Gli1 deletion prevents Helicobacter-induced gastric metaplasia and expansion of myeloid cell subsets.

Publications

Gli1 deletion prevents Helicobacter-induced gastric metaplasia and expansion of myeloid cell subsets.

Similar Datasets

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