title: Caspase-1-processed cytokines IL-1beta and IL-18 promote IL-17 production by gammadelta and CD4 T cells that mediate autoimmunity.
abstract: IL-1β plays a critical role in promoting IL-17 production by γδ and CD4 T cells. However, IL-1-targeted drugs, although effective against autoinflammatory diseases, are less effective against autoimmune diseases. Conversely, gain-of-function mutations in the NLRP3 inflammasome complex are associated with enhanced IL-1β and IL-18 production and Th17 responses. In this study, we examined the role of caspase-1-processed cytokines in IL-17 production and in induction of experimental autoimmune encephalomyelitis (EAE). Killed Mycobacterium tuberculosis, the immunostimulatory component in CFA used for inducing EAE, stimulated IL-1β and IL-18 production by dendritic cells through activation of the inflammasome complex and caspase-1. Dendritic cells stimulated with M. tuberculosis and myelin oligodendrocyte glycoprotein promoted IL-17 production by T cells and induced EAE following transfer to naive mice, and this was suppressed by a caspase-1 inhibitor and reversed by administration of IL-1β or IL-18. Direct injection of the caspase-1 inhibitor suppressed IL-17 production by CD4 T cells and γδ T cells in vivo and attenuated the clinical signs of EAE. γδ T cells expressed high levels of IL-18R and the combination of IL-18 and IL-23, as with IL-1β and IL-23, stimulated IL-17 production by γδ T cells, but also from CD4 T cells, in the absence of TCR engagement. Our findings demonstrate that caspase-1-processed cytokines IL-1β and IL-18 not only promote autoimmunity by stimulating innate IL-17 production by T cells but also reveal redundancy in the functions of IL-1β and IL-18, suggesting that caspase-1 or the inflammasome may be an important drug target for autoimmune diseases.
authors.affiliation: School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Lalor
authors.forename: Lara S
authors.initials: LS
authors.lastname: Dungan
authors.forename: Caroline E
authors.initials: CE
authors.lastname: Sutton
authors.forename: Sharee A
authors.initials: SA
authors.lastname: Basdeo
authors.forename: Jean M
authors.initials: JM
authors.lastname: Fletcher
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D020170:Caspase 1 / Q000378:metabolism*; D061945:Caspase Inhibitors; D003713:Dendritic Cells / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000276:immunology; D020382:Interleukin-18 / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology* / Q000378:metabolism; D053759:Interleukin-23 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000276:immunology; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D016133:Polymerase Chain Reaction; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D061945:Caspase Inhibitors; D020381:Interleukin-17; D020382:Interleukin-18; D053583:Interleukin-1beta; D053759:Interleukin-23; C571327:Mog protein, mouse; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D016692:Receptors, Antigen, T-Cell, gamma-delta; D020170:Caspase 1