Wiskott-Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells
| Autor: | Elisa Bonomi, Ulrich Kalinke, Stefania Gobessi, Anna Villa, Marco Catucci, Ayse Metin, Luigi D. Notarangelo, Francesca Prete, Sophie Hambleton, Maria Carmina Castiello, William Vermi, Robbert G. M. Bredius, Mayrel Labrada, Mirjam van der Burg, Federica Benvenuti, Caterina Cancrini, Alessandro Aiuti |
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| Přispěvatelé: | Immunology, International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy., Prete, Francesca, Catucci, Marco, Labrada, Mayrel, Gobessi, Stefania, Castiello Maria, Carmina, Bonomi, Elisa, Aiuti, Alessandro, Vermi, William, Cancrini, Caterina, Metin, Ayse, Hambleton, Sophie, Bredius, Robbert, Notarangelo Luigi, Daniele, van der Burg, Mirjam, Kalinke, Ulrich, Villa, Anna, Benvenuti, Federica |
| Rok vydání: | 2013 |
| Předmět: |
Male
Wiskott–Aldrich syndrome Autoimmunity Plasmacytoid dendritic cell Receptor Interferon alpha-beta Mice 0302 clinical medicine immune system diseases Interferon hemic and lymphatic diseases Immunology and Allergy Mice Knockout 0303 health sciences biology Wiskott–Aldrich syndrome protein hemic and immune systems Endocytosis Cell biology Wiskott-Aldrich Syndrome 3. Good health Interferon Type I Female Wiskott-Aldrich Syndrome Protein medicine.drug Signal Transduction congenital hereditary and neonatal diseases and abnormalities Immunology macromolecular substances Article 03 medical and health sciences medicine Animals Humans RNA Messenger 030304 developmental biology Innate immune system Base Sequence TLR9 Interferon-alpha Dendritic Cells Cell Biology medicine.disease Type I interferon production Actins Immunity Innate Mice Inbred C57BL Disease Models Animal Toll-Like Receptor 9 biology.protein Interferon type I 030215 immunology |
| Zdroj: | Journal of Experimental Medicine, 210(2), 355-374. Rockefeller University Press The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | Wiskott-Aldrich Syndrome protein (WASp)–mediated actin polymerization controls intracellular trafficking and compartmentalization of TLR9 ligands in plasmacytoid dendritic cells. Mutations in Wiskott-Aldrich syndrome (WAS) protein (WASp), a regulator of actin dynamics in hematopoietic cells, cause WAS, an X-linked primary immunodeficiency characterized by recurrent infections and a marked predisposition to develop autoimmune disorders. The mechanisms that link actin alterations to the autoimmune phenotype are still poorly understood. We show that chronic activation of plasmacytoid dendritic cells (pDCs) and elevated type-I interferon (IFN) levels play a role in WAS autoimmunity. WAS patients display increased expression of type-I IFN genes and their inducible targets, alteration in pDCs numbers, and hyperresponsiveness to TLR9. Importantly, ablating IFN-I signaling in WASp null mice rescued chronic activation of conventional DCs, splenomegaly, and colitis. Using WASp-deficient mice, we demonstrated that WASp null pDCs are intrinsically more responsive to multimeric agonist of TLR9 and constitutively secrete type-I IFN but become progressively tolerant to further stimulation. By acute silencing of WASp and actin inhibitors, we show that WASp-mediated actin polymerization controls intracellular trafficking and compartmentalization of TLR9 ligands in pDCs restraining exaggerated activation of the TLR9–IFN-α pathway. Together, these data highlight the role of actin dynamics in pDC innate functions and imply the pDC–IFN-α axis as a player in the onset of autoimmune phenomena in WAS disease. |
| Databáze: | OpenAIRE |
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