Wiskott-Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Castiello, Maria Carmina
Notarangelo, Luigi Daniele
van der Burg, Mirjam
MetadataShow full item record
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.
CitationWiskott-Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells. 2013, 210 (2):355-74 J. Exp. Med.
AffiliationInternational Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy.
The following license files are associated with this item:
- Neutrophils drive type I interferon production and autoantibodies in patients with Wiskott-Aldrich syndrome.
- Authors: Cervantes-Luevano KE, Caronni N, Castiello MC, Fontana E, Piperno GM, Naseem A, Uva P, Bosticardo M, Marcovecchio GE, Notarangelo LD, Cicalese MP, Aiuti A, Villa A, Benvenuti F
- Issue date: 2018 Nov
- Reduced type I interferon production by dendritic cells and weakened antiviral immunity in patients with Wiskott-Aldrich syndrome protein deficiency.
- Authors: Lang PA, Shaabani N, Borkens S, Honke N, Scheu S, Booth S, Brenner D, Meryk A, Barthuber C, Recher M, Mak TW, Ohashi PS, Häussinger D, Griffiths GM, Thrasher AJ, Bouma G, Lang KS
- Issue date: 2013 Mar
- Selective control of type I IFN induction by the Rac activator DOCK2 during TLR-mediated plasmacytoid dendritic cell activation.
- Authors: Gotoh K, Tanaka Y, Nishikimi A, Nakamura R, Yamada H, Maeda N, Ishikawa T, Hoshino K, Uruno T, Cao Q, Higashi S, Kawaguchi Y, Enjoji M, Takayanagi R, Kaisho T, Yoshikai Y, Fukui Y
- Issue date: 2010 Apr 12
- The chemotactic defect in wiskott-Aldrich syndrome macrophages is due to the reduced persistence of directional protrusions.
- Authors: Ishihara D, Dovas A, Park H, Isaac BM, Cox D
- Issue date: 2012
- The Wiskott-Aldrich syndrome: The actin cytoskeleton and immune cell function.
- Authors: Blundell MP, Worth A, Bouma G, Thrasher AJ
- Issue date: 2010