title: Inflammasome-independent role of apoptosis-associated speck-like protein containing a CARD (ASC) in T cell priming is critical for collagen-induced arthritis.
abstract: Rheumatoid arthritis is an autoimmune disease with 1% prevalence in the industrialized world. The contributions of the inflammasome components Nlrp3, ASC, and caspase-1 in the pathogenesis of collagen-induced arthritis have not been characterized. Here, we show that ASC(-/-) mice were protected from arthritis, whereas Nlrp3(-/-) and caspase-1(-/-) mice were susceptible to collagen-induced arthritis. Unlike Nlrp3(-/-) and caspase-1(-/-) mice, the production of collagen-specific antibodies was abolished in ASC(-/-) mice. This was due to a significantly reduced antigen-specific activation of lymphocytes by ASC(-/-) dendritic cells. Antigen-induced proliferation of purified ASC(-/-) T cells was restored upon incubation with wild type dendritic cells, but not when cultured with ASC(-/-) dendritic cells. Moreover, direct T cell receptor ligation with CD3 and CD28 antibodies induced a potent proliferation of ASC(-/-) T cells, indicating that ASC is specifically required in dendritic cells for antigen-induced T cell activation. Therefore, ASC fulfills a hitherto unrecognized inflammasome-independent role in dendritic cells that is crucial for T cell priming and the induction of antigen-specific cellular and humoral immunity and the onset of collagen-induced arthritis.
authors.affiliation: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Sirish K
authors.initials: SK
authors.lastname: Ippagunta
authors.forename: David D
authors.initials: DD
authors.lastname: Brand
authors.forename: Jiwen
authors.initials: J
authors.lastname: Luo
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Boyd
authors.forename: Christopher
authors.initials: C
authors.lastname: Calabrese
authors.forename: Rinke
authors.initials: R
authors.lastname: Stienstra
authors.forename: Frank L
authors.initials: FL
authors.lastname: Van de Veerdonk
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Mohamed
authors.initials: M
authors.lastname: Lamkanfi
authors.forename: Thirumala-Devi
authors.initials: TD
authors.lastname: Kanneganti
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001169:Arthritis, Experimental / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000096:biosynthesis; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology; D020170:Caspase 1 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D003094:Collagen / Q000276:immunology; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D001323:Autoantibodies; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; C498534:Pycard protein, mouse; D003094:Collagen; D020170:Caspase 1