Schlafen4 + -MDSC in Helicobacter -induced gastric metaplasia reveals role for GTPases.
| Autor: | Ding L; Department of Medicine-Gastroenterology, University of Arizona, Tucson, AZ, United States., Sheriff S; Department of Medicine-Gastroenterology, University of Arizona, Tucson, AZ, United States., Sontz RA; Department of Medicine-Gastroenterology, University of Arizona, Tucson, AZ, United States., Merchant JL; Department of Medicine-Gastroenterology, University of Arizona, Tucson, AZ, United States. |
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| Jazyk: | angličtina |
| Zdroj: | Frontiers in immunology [Front Immunol] 2023 Jun 02; Vol. 14, pp. 1139391. Date of Electronic Publication: 2023 Jun 02 (Print Publication: 2023). |
| DOI: | 10.3389/fimmu.2023.1139391 |
| Abstrakt: | Introduction: MDSCs 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. Methods: Single-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. Results: Slfn4 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. Conclusion: Taken 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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Ding, Sheriff, Sontz and Merchant.) |
| Databáze: | MEDLINE |
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