title: Wiskott-Aldrich syndrome protein-mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells.
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.
authors: International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy.
authors: Francesca
authors: F
authors: Prete
authors: Marco
authors: M
authors: Catucci
authors: Mayrel
authors: M
authors: Labrada
authors: Stefania
authors: S
authors: Gobessi
authors: Maria Carmina
authors: MC
authors: Castiello
authors: Elisa
authors: E
authors: Bonomi
authors: Alessandro
authors: A
authors: Aiuti
authors: William
authors: W
authors: Vermi
authors: Caterina
authors: C
authors: Cancrini
authors: Ayse
authors: A
authors: Metin
authors: Sophie
authors: S
authors: Hambleton
authors: Robbert
authors: R
authors: Bredius
authors: Luigi Daniele
authors: LD
authors: Notarangelo
authors: Mirjam
authors: M
authors: van der Burg
authors: Ulrich
authors: U
authors: Kalinke
authors: Anna
authors: A
authors: Villa
authors: Federica
authors: F
authors: Benvenuti
mesh_terms: D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D015551:Autoimmunity; D001483:Base Sequence; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004705:Endocytosis; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000096:biosynthesis* / Q000235:genetics; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D014923:Wiskott-Aldrich Syndrome / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051316:Wiskott-Aldrich Syndrome Protein / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; C508034:Ifnar2 protein, mouse; D007370:Interferon Type I; D016898:Interferon-alpha; D012333:RNA, Messenger; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C495768:Was protein, mouse; D051316:Wiskott-Aldrich Syndrome Protein; D053633:Receptor, Interferon alpha-beta