IL-23 and the Th17 pathway promote inflammation and impair antifungal immune resistance.
Although inflammation is an essential component of the protective response to fungi, its dysregulation may significantly worsen fungal diseases. We found here that the IL-23/IL-17 developmental pathway acted as a negative regulator of the Th1-mediated immune resistance to fungi and played an inflammatory role previously attributed to uncontrolled Th1 cell responses. Both inflammation and infection were exacerbated by a heightened Th17 response against Candida albicans and Aspergillus fumigatus, two major human fungal pathogens. IL-23 acted as a molecular connection between uncontrolled fungal growth and inflammation, being produced by dendritic cells in response to a high fungal burden and counter-regulating IL-12p70 production. Both IL-23 and IL-17 subverted the inflammatory program of neutrophils, which resulted in severe tissue inflammatory pathology associated with infection. Our data are the first demonstrating that the IL-23/IL-17 pathway promotes inflammation and susceptibility in an infectious disease model. As IL-23-driven inflammation promotes infection and impairs antifungal resistance, modulation of the inflammatory response represents a potential strategy to stimulate protective immune responses to fungi.
Zelante
Teresa
T
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
De Luca
Antonella
A
Bonifazi
Pierluigi
P
Montagnoli
Claudia
C
Bozza
Silvia
S
Moretti
Silvia
S
Belladonna
Maria L
ML
Vacca
Carmine
C
Conte
Carmela
C
Mosci
Paolo
P
Bistoni
Francesco
F
Puccetti
Paolo
P
Kastelein
Robert A
RA
Kopf
Manfred
M
Romani
Luigina
L
D000818:Animals; D001228:Aspergillosis / Q000276:immunology* / Q000473:pathology; D001232:Aspergillus fumigatus / Q000276:immunology; D002176:Candida albicans / Q000276:immunology; D002177:Candidiasis / Q000276:immunology* / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D007113:Immunity, Innate; D007249:Inflammation / Q000276:immunology; D020381:Interleukin-17 / Q000502:physiology*; D053759:Interleukin-23 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology*
D020381:Interleukin-17; D053759:Interleukin-23