title: Lack of Toll IL-1R8 exacerbates Th17 cell responses in fungal infection.
abstract: TLRs contribute to the inflammatory response in fungal infections. Although inflammation is an essential component of the protective response to fungi, its dysregulation may significantly worsen fungal diseases. In this study, we tested the hypothesis that Toll IL-1R8 (TIR8)/single Ig IL-1-related receptor, a member of the IL-1R family acting as a negative regulator of TLR/IL-1R signaling, affects TLR responses in fungal infections. Genetically engineered Tir8(-/-) mice were assessed for inflammatory and adaptive Th cell responses to Candida albicans and Aspergillus fumigatus. Inflammatory pathology and susceptibility to infection were higher in Tir8(-/-) mice and were causally linked to the activation of the Th17 pathway. IL-1R signaling was involved in Th17 cell activation by IL-6 and TGF-beta in that limited inflammatory pathology and relative absence of Th17 cell activation were observed in IL-1RI(-/-) mice. These data demonstrate that TIR8 is required for host resistance to fungal infections and that it functions to negatively regulate IL-1-dependent activation of inflammatory Th17 responses. TIR8 may contribute toward fine-tuning the balance between protective immunity and immunopathology in infection.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bozza
authors.forename: Teresa
authors.initials: T
authors.lastname: Zelante
authors.forename: Silvia
authors.initials: S
authors.lastname: Moretti
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Bonifazi
authors.forename: Antonella
authors.initials: A
authors.lastname: DeLuca
authors.forename: Carmen
authors.initials: C
authors.lastname: D'Angelo
authors.forename: Gloria
authors.initials: G
authors.lastname: Giovannini
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garlanda
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.forename: Francesco
authors.initials: F
authors.lastname: Bistoni
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.forename: Luigina
authors.initials: L
authors.lastname: Romani
mesh_terms: D000818:Animals; D001228:Aspergillosis / Q000235:genetics / Q000276:immunology; D002177:Candidiasis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology*; D008172:Lung Diseases, Fungal / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism*
chemical_list: D007375:Interleukin-1; D020381:Interleukin-17; D017472:Receptors, Interleukin-1; C484529:SIGIRR protein, mouse