A type I interferon regulatory network for human plasmacytoid dendritic cells based on heparin, membrane- bound and soluble BDCA-2

• 成果类型: Article
• 署名作者: Solis, Francisco Venegas-; Staliunaite, Laura; Rudolph, Elisa; Muench, Carina Chan - Song; Yu, Philipp; Freibert, Sven - A.; Maeda, Takahiro; Zimmer, Christine L.; Moebs, Christian; Keller, Christian; Kaufmann, Andreas; Bauer, Stefan
• 署名单位: Philipps University Marburg; Philipps University Marburg; Philipps University Marburg; Philipps University Marburg; Nagasaki University; Philipps University Marburg
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11643
• DOI: 10.1073/pnas.2312404121
• 发表日期: 2024-03-19
• 关键词: scrub typhus; binding; lectin; receptor; alpha; inhibitor; signals; antigen; FAMILY; domain

摘要

Plasmacytoid dendritic cells (pDCs) produce type I interferons (IFNs) after sensing viral/bacterial RNA or DNA by toll - like receptor (TLR) 7 or TLR9, respectively. However, aberrant pDCs activation can cause adverse effects on the host and contributes to the pathogenesis of type I IFN- related autoimmune diseases. Here, we show that heparin interacts with the human pDCs- specific blood dendritic cell antigen 2 (BDCA-2) but not with related lectins such as DCIR or dectin-2. Importantly, BDCA-2-heparin interaction depends on heparin sulfation and receptor glycosylation and results in inhibition of TLR9- driven type I IFN production in primary human pDCs and the pDC-like cell line CAL - 1. This inhibition is mediated by unfractionated and low- molecular- weight heparin, as well as endogenous heparin from plasma, suggesting that the local blood environment controls the production of IFN-alpha in pDCs. Additionally, we identified an activation- dependent soluble form of BDCA-2 (solBDCA-2) in human plasma that functions as heparin antagonist and thereby increases TLR9- driven IFN-alpha production in pDCs. Of importance, solBDCA-2 levels in the serum were increased in patients with scrub typhus (an acute infectious disease caused by Orientia tsutsugamushi) compared to healthy control subjects and correlated with anti-dsDNA antibodies titers. In contrast, solBDCA-2 levels in plasma from patients with bullous pemphigoid or psoriasis were reduced. In summary, this work identifies a regulatory network consisting of heparin, membrane - bound and solBDCA-2 modulating TLR9- driven IFN-alpha production in pDCs. This insight into pDCs function and regulation may have implications for the treatment of pDCs- related autoimmune diseases.