Voltage-Gated Proton Channel Hv1 Controls TLR9 Activation in Plasmacytoid Dendritic Cells
| Autor: | Simone Bauer, Jan Broder Engler, Nina Kursawe, Marcel S Woo, Michael Moles, Friederike Ufer, Britta Huscher, Elena Montes-Cobos, Lars Binkle, Manuel A. Friese |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Voltage-gated proton channel
Endosome Immunology medicine.disease_cause Ion Channels Autoimmunity 03 medical and health sciences Mice 0302 clinical medicine In vivo medicine Immunology and Allergy Animals Secretion Innate immune system Chemistry TLR9 Interferon-alpha hemic and immune systems Dendritic Cells In vitro Immunity Innate Cell biology Mice Inbred C57BL Oligodeoxyribonucleotides Toll-Like Receptor 9 Reactive Oxygen Species 030215 immunology Signal Transduction |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 205(11) |
| ISSN: | 1550-6606 |
| Popis: | The voltage-gated proton channel Hv1 regulates proton fluxes across membranes, thereby influencing pH-dependent processes. Plasmacytoid dendritic cells (pDCs) require a particularly tight regulation of endosomal pH to ensure strong type I IFN secretion exclusively during infection, avoiding autoimmunity. However, whether Hv1 is important for pH control in pDCs is presently unknown. In this study, we show that mouse pDCs require Hv1 to achieve potent type I IFN responses after the recognition of foreign DNA by endosomal TLR9. Genetic disruption of Hvcn1, which encodes Hv1, impaired mouse pDC activation by CpG oligonucleotides in vitro and in vivo, reducing IFN-α secretion and the induction of IFN-stimulated genes. Mechanistically, Hvcn1 deficiency delayed endosomal acidification and enhanced intracellular reactive oxygen species production, consequently limiting protease activity and TLR9 signaling. Our study reveals a critical role of Hv1 during innate immune responses and places this channel as a key modulator of type I IFN production, the hallmark function of pDCs, commending Hv1 as an attractive target for modulating type I IFN–driven autoimmunity. |
| Databáze: | OpenAIRE |
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