Toll-like Receptor 9 Pathway Mediates Schlafen+-MDSC Polarization During Helicobacter-induced Gastric Metaplasias

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 163; no. 2; pp. 411 - 425.e4
• Main Authors: Ding, Lin, Chakrabarti, Jayati, Sheriff, Sulaiman, Li, Qian, Thi Hong, Hahn Nguyen, Sontz, Ricky A., Mendoza, Zoe E., Schreibeis, Amanda, Helmrath, Michael A., Zavros, Yana, Merchant, Juanita L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2022
• Subjects: 2-D Organoid-Derived Monolayer; Animals; DAMPs; Helicobacter; Helicobacter Infections - genetics; Helicobacter Infections - metabolism; Humans; IFNα; Interferon-alpha; Metaplasia; Mice; Myeloid-Derived Suppressor Cells; NF-kappa B - metabolism; Plasmacytoid Dendritic Cells; SPEM; Stomach Neoplasms - genetics; Stomach Neoplasms - microbiology; Toll-Like Receptor 4; Toll-Like Receptor 9 - genetics; Toll-Like Receptor 9 - metabolism; 2-D Organoid-Derived Monolayer; TNFα; MDSC; SLFN; DAMPs; IFN; NF-κB; SNP; ANOVA; TLR; IF; PBS; IFNα; Plasmacytoid Dendritic Cells; SPEM; IM; GAC; AEM; 2-D; CEM; CFSE; GIM; α-IFNα; CdM; PBMC; pDC; IRF7; CTL; DAMP; ELISA
• ISSN: 0016-5085; 1528-0012; 1528-0012
• DOI: 10.1053/j.gastro.2022.04.031

A subset of myeloid-derived suppressor cells (MDSCs) that express murine Schlafen4 (SLFN4) or its human ortholog SLFN12L polarize in the Helicobacter-inflamed stomach coincident with intestinal or spasmolytic polypeptide-expressing metaplasia. We propose that individuals with a more robust response to damage-activated molecular patterns and increased Toll-like receptor 9 (TLR9) expression are predisposed to the neoplastic complications of Helicobacter infection. A mouse or human Transwell co-culture system composed of dendritic cells (DCs), 2-dimensional gastric epithelial monolayers, and Helicobacter were used to dissect the cellular source of interferon-α (IFNα) in the stomach by flow cytometry. Conditioned media from the co-cultures polarized primary myeloid cells. MDSC activity was determined by T-cell suppression assays. In human subjects with intestinal metaplasia or gastric cancer, the rs5743836 TLR9T>C variant was genotyped and linked to TLR9, IFNα, and SLFN12L expression by immunohistochemistry. Nuclear factor-κB binding to the TLR9 C allele was determined by electrophoretic mobility shift assays. Helicobacter infection induced gastric epithelial and plasmacytoid DC expression of TLR9 and IFNα. Co-culturing primary mouse or human cells with DCs and Helicobacter induced TLR9, IFNα secretion, and SLFN+-MDSC polarization. Neutralizing IFNα in vivo mitigated Helicobacter-induced spasmolytic polypeptide-expressing metaplasia. The TLR9 minor C allele creates a nuclear factor-κB binding site associated with higher levels of TLR9, IFNα, and SLFN12L in Helicobacter-infected stomachs that correlated with a greater incidence of metaplasias and cancer. TLR9 plays an essential role in the production of IFNα and polarization of SLFN+ MDSCs on Helicobacter infection. Subjects carrying the rs5743836 TLR9 minor C allele are predisposed to neoplastic complications if chronically infected. [Display omitted] Some Helicobacter pylori–infected subjects have a genetic tendency to develop an aggressive immune response to bacterial and cellular debris that accumulates in the inflamed microenvironment, ultimately leading to pre-neoplastic sequelae.