IL-9 Integrates the Host-Candida Cross-Talk in Vulvovaginal Candidiasis to Balance Inflammation and Tolerance.

Giorgia Renga,Luigina Romani,Claudio Costantini,Andrea Bartoli,Monica Borghi,Paolo Mosci,Jean-Christophe Renauld,Vasileios Oikonomou

doi:10.3389/fimmu.2018.02702

Giorgia Renga, Luigina Romani + Show 6 more

Open Access

https://doi.org/10.3389/fimmu.2018.02702

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Abstract

Vulvovaginal candidiasis (VVC) is a common fungal infection caused by Candida albicans. The antifungal therapy represents the standard of care but due to the high costs of treatment and to the inability to prevent recurrences, the development of alternative therapeutic approaches is much-awaited. Recently, we have shown that the pathogenesis of C. albicans in the gut is modulated by IL-9, a pleiotropic cytokine able to promote both inflammation and tolerance during C. albicans infection. Herein, by using a mouse model of VVC, we similarly demonstrated that IL-9 might exert a dual role in VVC by contributing to inflammation during the initial immune activation and promoting resolution thereafter. Specifically, IL-9 has a pro-inflammatory activity at the onset of VVC by promoting NLRP3 inflammasome activity and mucosal mast cells expansion but a tolerogenic role in the resolution phase by promoting IL-1Ra production and connective tissue mast cells activation. We further show that a timely IL-9 neutralization at the onset of the inflammatory response ameliorated symptoms and vaginal pathology. Given that vaginal fluids from patients with recurrent VVC had higher levels of IL-9, these findings, by providing novel insights into the pathogenesis of VVC, may pave the way for alternative therapeutic strategies based on IL-9 neutralization.

Highlights

The delicate balance between immune resistance and tolerance toward Candida albicans, an opportunistic fungus commonly present in human mucosal surfaces, is pivotal to limit inflammation and maintain homeostasis
In C57BL/6 mice, the initial activation of NLR family Pyrin domain containing 3 (NLRP3) was counteracted by an increased production of IL-22 that led to NLR family CARD domain-containing protein 4 (NLRC4)-dependent production of IL-1Ra
Whatever the mechanism of regulation, this finding is consistent with the observation that IL-1Ra expression becomes refractory to prolonged inducing signals [8]. These data suggest that IL-9 participates in the timely regulation of inflammasome activity that takes place during vulvovaginal candidiasis (VVC) and that interference with IL-9 signaling might disrupt this auto-regulated circuit and promote an unrestrained inflammation

Summary

Introduction

The delicate balance between immune resistance and tolerance toward Candida albicans, an opportunistic fungus commonly present in human mucosal surfaces, is pivotal to limit inflammation and maintain homeostasis. The high costs of treatment and the inability to prevent recurrences, currently limit the use of antifungals and make the development of alternative therapeutic approaches much-awaited [3]. IL-9 is a pleiotropic cytokine that targets different hematopoietic cells and plays a central role at mucosal sites by promoting both inflammation and protection. We have recently shown that IL-9 is able to modulate the ability of C. albicans to switch from commensal to pathogen in the gastrointestinal tract [4]. A gender-specific effect seems to underlie the pathogenic role

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