Pathogenic NLRP3 Inflammasome Activity during Candida Infection Is Negatively Regulated by IL-22 via Activation of NLRC4 and IL-1Ra.
Candida albicans is a well-tolerated resident of human mucosal tissues. This implies that host defense mechanisms cooperate to limit inflammation while controlling fungal burden. The cytokine IL-22 and inflammasomes are essential components of the mucosal responses to C. albicans. How these components cooperate to mediate the balance of inflammation and host defense is not explored. We find that NLRP3 inflammasome activation promotes neutrophil recruitment and inflammation during infection and that this activity is counteracted by IL-22. Mechanistically, IL-22 activated NLRC4 for sustained production of the IL-1 receptor antagonist IL-1Ra, which restrained NLRP3 activity. Symptomatic infection in mice and humans occurred under conditions of IL-1Ra deficiency and was rescued in mice by replacement therapy with the recombinant IL-1Ra anakinra. Thus, pathogenic inflammasome activity during Candida infection is negatively regulated by the IL-22/NLRC4/IL-1Ra axis. Our findings offer insights into the pathogenesis of C. albicans and suggest therapeutic avenues for candidiasis.
Department of Experimental Medicine, University of Perugia, Polo Unico Sant'Andrea delle Fratte, 06132 Perugia, Italy.
Monica
M
Borghi
Department of Experimental Medicine, University of Perugia, Polo Unico Sant'Andrea delle Fratte, 06132 Perugia, Italy.
Antonella
A
De Luca
Department of Experimental Medicine, University of Perugia, Polo Unico Sant'Andrea delle Fratte, 06132 Perugia, Italy.
Matteo
M
Puccetti
Department of Medicine, Radboud University, Medical Centre, 6500 HB, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, 6500 HB, Nijmegen, The Netherlands.
Martin
M
Jaeger
Department of Experimental Medicine, University of Perugia, Polo Unico Sant'Andrea delle Fratte, 06132 Perugia, Italy.
Antonella
A
Mencacci
Department of Experimental Medicine, University of Perugia, Polo Unico Sant'Andrea delle Fratte, 06132 Perugia, Italy.
Vasilis
V
Oikonomou
Department of Experimental Medicine, University of Perugia, Polo Unico Sant'Andrea delle Fratte, 06132 Perugia, Italy.
Marilena
M
Pariano
Humanitas Clinical and Research Center, 20089 Rozzano, Milan, Italy.
Cecilia
C
Garlanda
Department of Experimental Medicine, University of Perugia, Polo Unico Sant'Andrea delle Fratte, 06132 Perugia, Italy.
Silvia
S
Moretti
Department of Experimental Medicine, University of Perugia, Polo Unico Sant'Andrea delle Fratte, 06132 Perugia, Italy.
Andrea
A
Bartoli
Infectious Diseases, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Jack
J
Sobel
Department of Medicine, Radboud University, Medical Centre, 6500 HB, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, 6500 HB, Nijmegen, The Netherlands.
Frank L
FL
van de Veerdonk
Radboud Center for Infectious Diseases, 6500 HB, Nijmegen, The Netherlands; Division of Infectious Diseases, University of Colorado Denver, Aurora, CO 80045, USA.
Charles A
CA
Dinarello
Department of Medicine, Radboud University, Medical Centre, 6500 HB, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, 6500 HB, Nijmegen, The Netherlands.
Mihai G
MG
Netea
Department of Experimental Medicine, University of Perugia, Polo Unico Sant'Andrea delle Fratte, 06132 Perugia, Italy. Electronic address: luigina.romani@unipg.it.
Luigina
L
Romani
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002176:Candida albicans / Q000276:immunology*; D002177:Candidiasis / Q000276:immunology / Q000473:pathology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000172:deficiency / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000097043:Interleukin-22
D051017:Apoptosis Regulatory Proteins; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D007378:Interleukins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000097043:Interleukin-22; C512299:Ipaf protein, mouse; C453881:NLRP3 protein, human