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

作者：Lin Ding, Jayati Chakrabarti, Sulaiman Sheriff, Qian Li, Hahn Nguyen Thi Hong, Ricky Sontz, Zoe Mendoza, Amanda Schreibeis, Michael A. Helmrath, Yana Zavros, Juanita L. Merchant · 发表于：Gastroenterology · 年份：2022 · DOI：10.1053/j.gastro.2022.04.031 · 被引用次数：52 · 研究领域：Immune cells in cancer、Inflammation biomarkers and pathways、Immune responses and vaccinations

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: -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...