title: The IL-36 receptor pathway regulates Aspergillus fumigatus-induced Th1 and Th17 responses.
abstract: IL-1 drives Th responses, particularly Th17, in host defense. Sharing the same co-receptor, the IL-1 family member IL-36 exhibits properties similar to those of IL-1. In the present study, we investigated the role of IL-36 in Aspergillus fumigatus-induced human Th responses. We observed that different morphological forms of A. fumigatus variably increase steady-state mRNA of IL-36 subfamily members. IL-36α is not significantly induced by any morphological form of Aspergillus. Most strikingly, IL-36γ is significantly induced by live A. fumigatus conidia and heat-killed hyphae, whereas IL-36Ra (IL-36 receptor antagonist) is significantly induced by heat-killed conidia, hyphae, and live conidia. We also observed that IL-36γ expression is dependent on the dectin-1/Syk and TLR4 signaling pathway. In contrast, TLR2 and CR3 inhibit IL-36γ expression. The biological relevance of IL-36 induction by Aspergillus is demonstrated by experiments showing that inhibition of the IL-36 receptor by IL-36Ra reduces Aspergillus-induced IL-17 and IFN-γ. These data describe that IL-36-dependent signals are a novel cytokine pathway that regulates Th responses induced by A. fumigatus, and demonstrate a role for TLR4 and dectin-1 in the induction of IL-36γ.
authors.affiliation: Department of Medicine, Radboud University Nijmegen Medical Centre and Nijmegen Institute for Infection, Inflammation, and Immunity, Nijmegen, The Netherlands.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Gresnigt
authors.forename: Berenice
authors.initials: B
authors.lastname: Rösler
authors.forename: Cor W M
authors.initials: CW
authors.lastname: Jacobs
authors.forename: Katharina L
authors.initials: KL
authors.lastname: Becker
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.forename: Jos W M
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
authors.forename: Frank L
authors.initials: FL
authors.lastname: van de Veerdonk
mesh_terms: D001228:Aspergillosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D001232:Aspergillus fumigatus / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D025301:Hyphae / Q000276:immunology; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D013172:Spores, Fungal / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000099181:Dectin-1
chemical_list: D051858:Forkhead Transcription Factors; D007371:Interferon-gamma; D020381:Interleukin-17; D037181:Lectins, C-Type; D016177:Macrophage-1 Antigen; D012333:RNA, Messenger; D018123:Receptors, Interleukin; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C546929:CLEC7A protein, human; D000099181:Dectin-1; C418974:FOXP3 protein, human; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C571244:interleukin-36 receptor, human