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

Autor:	Venegas-Solis F; Institute for Immunology, Philipps-Universität Marburg, Biomedizinisches Forschungszentrum Marburg, Marburg 35043, Germany., Staliunaite L; Institute for Immunology, Philipps-Universität Marburg, Biomedizinisches Forschungszentrum Marburg, Marburg 35043, Germany., Rudolph E; Institute for Immunology, Philipps-Universität Marburg, Biomedizinisches Forschungszentrum Marburg, Marburg 35043, Germany., Münch CC; Institute of Virology, Philipps-Universität Marburg, Biomedizinisches Forschungszemtrum Marburg, Marburg 35043, Germany., Yu P; Institute for Immunology, Philipps-Universität Marburg, Biomedizinisches Forschungszentrum Marburg, Marburg 35043, Germany., Freibert SA; Institute for Cytobiology, Center for Synthetic Microbiology, Philipps-Universität Marburg, Marburg 35032, Germany.; Core Facility 'Protein Biochemistry and Spectroscopy', Philipps-Universität Marburg, Marburg 35032, Germany., Maeda T; Department of Island and Community Medicine, Island Medical Research Institute, Nagasaki University Graduate School of Biomedical Science, Nagasaki 852-8523, Japan., Zimmer CL; Department of Dermatology and Allergology, Philipps-Universität Marburg, Marburg 35043, Germany., Möbs C; Department of Dermatology and Allergology, Philipps-Universität Marburg, Marburg 35043, Germany., Keller C; Institute of Virology, Philipps-Universität Marburg, Biomedizinisches Forschungszemtrum Marburg, Marburg 35043, Germany., Kaufmann A; Institute for Immunology, Philipps-Universität Marburg, Biomedizinisches Forschungszentrum Marburg, Marburg 35043, Germany., Bauer S; Institute for Immunology, Philipps-Universität Marburg, Biomedizinisches Forschungszentrum Marburg, Marburg 35043, Germany.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Mar 19; Vol. 121 (12), pp. e2312404121. Date of Electronic Publication: 2024 Mar 13.
DOI:	10.1073/pnas.2312404121
Abstrakt:	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-α 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-α 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-α production in pDCs. This insight into pDCs function and regulation may have implications for the treatment of pDCs-related autoimmune diseases. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
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