Lin Ding1, Jayati Chakrabarti2, Sulaiman Sheriff1, Qian Li3, Hahn Nguyen Thi Hong4, Ricky A Sontz1, Zoe E Mendoza1, Amanda Schreibeis5, Michael A Helmrath5, Yana Zavros2, Juanita L Merchant6. 1. Department of Medicine-Gastroenterology & Hepatology, University of Arizona, Tucson, Arizona. 2. Department of Cellular & Molecular Medicine, University of Arizona, Tucson, Arizona. 3. Department of Gastroenterology, Xiangya Hospital Central South University, Changsha, Hunan, China. 4. Dinh Tien Hoang Institute of Medicine, Vietnam Union of Science and Technology Association, Institute of Biotechnology, Hanoi, Vietnam. 5. Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 6. Department of Medicine-Gastroenterology & Hepatology, University of Arizona, Tucson, Arizona. Electronic address: jmerchant@arizona.edu.
Abstract
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: 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. CONCLUSIONS: 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.
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: 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. CONCLUSIONS: 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.
Authors: Nina Bertaux-Skeirik; Rui Feng; Michael A Schumacher; Jing Li; Maxime M Mahe; Amy C Engevik; Jose E Javier; Richard M Peek; Karen Ottemann; Veronique Orian-Rousseau; Gregory P Boivin; Michael A Helmrath; Yana Zavros Journal: PLoS Pathog Date: 2015-02-06 Impact factor: 6.823
Authors: Constantinos P Zambirinis; Elliot Levie; Susanna Nguy; Antonina Avanzi; Rocky Barilla; Yijie Xu; Lena Seifert; Donnele Daley; Stephanie H Greco; Michael Deutsch; Saikiran Jonnadula; Alejandro Torres-Hernandez; Daniel Tippens; Smruti Pushalkar; Andrew Eisenthal; Deepak Saxena; Jiyoung Ahn; Cristina Hajdu; Dannielle D Engle; David Tuveson; George Miller Journal: J Exp Med Date: 2015-10-19 Impact factor: 14.307
Authors: Lin Ding; Qian Li; Jayati Chakrabarti; Andres Munoz; Emmanuelle Faure-Kumar; Ramon Ocadiz-Ruiz; Nataliya Razumilava; Guiying Zhang; Michael H Hayes; Ricky A Sontz; Zoe Elena Mendoza; Swapna Mahurkar; Joel K Greenson; Guillermo Perez-Perez; Nguyen Thi Hong Hanh; Yana Zavros; Linda C Samuelson; Dimitrios Iliopoulos; Juanita L Merchant Journal: Gut Date: 2020-01-24 Impact factor: 23.059