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.

Pathogenic NLRP3 Inflammasome Activity during Candida Infection Is Negatively Regulated by IL-22 via Activation of NLRC4 and IL-1Ra

BORGHI, MONICA;DE LUCA, ANTONELLA;MENCACCI, Antonella;PARIANO, MARILENA;MORETTI, SILVIA;BARTOLI, Andrea;ROMANI, Luigina;OIKONOMOU, VASILEIOS
2015

Abstract

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.
2015
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11391/1355992
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