Wiskott-Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells.

2.50
Hdl Handle:
http://hdl.handle.net/10033/297038
Title:
Wiskott-Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells.
Authors:
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 ( 0000-0003-0503-9564 ) ; Villa, Anna; Benvenuti, Federica
Abstract:
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.
Affiliation:
International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy.
Citation:
Wiskott-Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells. 2013, 210 (2):355-74 J. Exp. Med.
Journal:
The Journal of experimental medicine
Issue Date:
11-Feb-2013
URI:
http://hdl.handle.net/10033/297038
DOI:
10.1084/jem.20120363
PubMed ID:
23337808
Type:
Article
Language:
en
ISSN:
1540-9538
Appears in Collections:
publications of the department of experimental infection research ([TC] EXPI)

Full metadata record

DC FieldValue Language
dc.contributor.authorPrete, Francescaen_GB
dc.contributor.authorCatucci, Marcoen_GB
dc.contributor.authorLabrada, Mayrelen_GB
dc.contributor.authorGobessi, Stefaniaen_GB
dc.contributor.authorCastiello, Maria Carminaen_GB
dc.contributor.authorBonomi, Elisaen_GB
dc.contributor.authorAiuti, Alessandroen_GB
dc.contributor.authorVermi, Williamen_GB
dc.contributor.authorCancrini, Caterinaen_GB
dc.contributor.authorMetin, Ayseen_GB
dc.contributor.authorHambleton, Sophieen_GB
dc.contributor.authorBredius, Robberten_GB
dc.contributor.authorNotarangelo, Luigi Danieleen_GB
dc.contributor.authorvan der Burg, Mirjamen_GB
dc.contributor.authorKalinke, Ulrichen_GB
dc.contributor.authorVilla, Annaen_GB
dc.contributor.authorBenvenuti, Federicaen_GB
dc.date.accessioned2013-07-25T10:40:02Zen
dc.date.available2013-07-25T10:40:02Zen
dc.date.issued2013-02-11en
dc.identifier.citationWiskott-Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells. 2013, 210 (2):355-74 J. Exp. Med.en_GB
dc.identifier.issn1540-9538en
dc.identifier.pmid23337808en
dc.identifier.doi10.1084/jem.20120363en
dc.identifier.urihttp://hdl.handle.net/10033/297038en
dc.description.abstractMutations 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.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to The Journal of experimental medicineen_GB
dc.subject.meshActinsen_GB
dc.subject.meshAnimalsen_GB
dc.subject.meshAutoimmunityen_GB
dc.subject.meshBase Sequenceen_GB
dc.subject.meshDendritic Cellsen_GB
dc.subject.meshDisease Models, Animalen_GB
dc.subject.meshEndocytosisen_GB
dc.subject.meshFemaleen_GB
dc.subject.meshHumansen_GB
dc.subject.meshImmunity, Innateen_GB
dc.subject.meshInterferon Type Ien_GB
dc.subject.meshInterferon-alphaen_GB
dc.subject.meshMaleen_GB
dc.subject.meshMiceen_GB
dc.subject.meshMice, Inbred C57BLen_GB
dc.subject.meshMice, Knockouten_GB
dc.subject.meshRNA, Messengeren_GB
dc.subject.meshReceptor, Interferon alpha-betaen_GB
dc.subject.meshSignal Transductionen_GB
dc.subject.meshToll-Like Receptor 9en_GB
dc.subject.meshWiskott-Aldrich Syndromeen_GB
dc.subject.meshWiskott-Aldrich Syndrome Proteinen_GB
dc.titleWiskott-Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells.en
dc.typeArticleen
dc.contributor.departmentInternational Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy.en_GB
dc.identifier.journalThe Journal of experimental medicineen_GB

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