gms | German Medical Science

Introduction: Candida albicans is the most important cause of invasive fungal infections in humans and is associated with high morbidity and mortality. Moreover, the frequency of invasive mycoses due to opportunistic fungal pathogens has been significantly growing in intensive care units during the last two decades.

As shown for Candida-induced sepsis in mice models, the immune response rather than the pathogen itself is responsible for the fatal host damage. Therefore, modulation of the immune response is crucial during the early stage of invasive candidiasis. In this sense, several nuclear receptors (NRs) possess the ability to regulate immune responses to inflammatory signals. Indeed, it has been shown that the Vitamin D receptor is able to modulate the Candida-induced cytokine production by regulating the expression and function of several fungal Pattern Recognition Receptors (PRRs). Nevertheless, little is known about molecular determinants of the crosstalk between other NRs and PRRs-dependent immune responses during fungal infections.

Objectives: In the present study, we aimed to analyze the impact of different NR-agonists on the cytokine production of human monocytes upon C. albicans infection, as well as its ability to modulate the expression of relevant PRRs.

Method: Monocytes were isolated from human buffy coats, and stimulated with C. albicans in presence or absence of different NR-agonists, including Vitamin A-metabolites and 17β-Estradiol, among others. The modulatory role of the NRs on the immune response was characterized at transcriptional level by quantitative RT-PCR including numerous genes involved in the anti-fungal response. Cytokine–release was measured in the cell culture supernatants using specific ELISAs, whereas the expression of C. albicans relevant-PRRs was assessed by flow cytometry.

Results: Several NR-agonists were able to abrogate the C.albicans-induced cytokine expression and release, as shown at transcriptional and post-translational level. In particular, activation of retinoic acid receptors led to a strong inhibition of the TNFα, IL-6, IL-12 and IFNβ response. Moreover, these NRs were also able to down-regulate the expression of several PRR involved in the anti-fungal response.

Conclusion: As our results show, nuclear receptors such as RARs, are able to modulate the expression of surface PRR as well as the release of several cytokines in human monocytes upon C. albicans challenge.