Multiple Signaling Pathways Involved in Human Dendritic Cell Maturation Are Affected by the Fungal Quorum-Sensing Molecule Farnesol

Abstract

The quorum-sensing molecule farnesol is produced by the opportunistic human fungal pathogen Candida albicans. Aside from its primary function of blocking the transition from yeast to hyphal morphotype, it has an immunomodulatory role on human dendritic cells (DC) through the alteration of surface markers, cytokine secretion, and their ability to activate T cells. Nonetheless, the molecular mechanisms by which farnesol modulates DC differentiation and maturation remained unknown. In this study, we demonstrate through transcriptional and functional assays that farnesol influences several signaling pathways during DC differentiation and in response to TLR agonists. In particular, farnesol increases the expression of the Ag-presenting glycoprotein CD1d through the nuclear receptors PPARg and RARa, as well as p38 MAPK. However, the higher expression of CD1d did not confer these DC with an enhanced capacity to activate CD1d-restricted invariant NKT cells. In the presence of farnesol, there is reduced secretion of the Th1-inducing cytokine, IL-12, and increased release of proinflammatory cytokines, as well as the anti-inflammatory cytokine IL-10. These changes are partially independent of nuclear receptor activity but, in the case of TNF-a and IL-10, dependent on NF-kB and MAPK pathways. Interestingly, renewal of the IL-12/IL-10 milieu restores the ability of farnesol-differentiated DC to activate invariant NKT, Th1, and FOXP3 + regulatory T cells. Our results show that farnesol modulates nuclear receptors, NF-kB, and MAPK-signaling pathways, thereby impairing the capacity of DC to activate several T cells subsets and potentially conferring C. albicans, an advantage in overcoming DC-mediated immunity.

Effects of Farnesol on Drug-Resistant and Non-Resistant <i>Candida albicans</i>: Implications for Cosmetic and Pharmaceutical Applications

“…During its growth, Candida albicans produces the sesquiterpene alcohol farnesol, which among other compounds is an autoinducer of quorum sensing, upregulating virulence genes related to biofilm formation and influencing morphogenesis among many other biological activities [11]. While quorum sensing is a naturally occurring process that helps assure survival, farnesol displays other disparate properties including those directed at human host, modulating immune reactions [12] and enhancing innate immune reactions [13]. Farnesol may also modulate efflux pump activity altering response to antifungal drugs although up or down regulation may relate to concentration [6] [7].…”

Cell Communications among Microorganisms, Plants, and Animals: Origin, Evolution, and Interplays

“…Yeasts also communicate via soluble molecules that can diffuse and affect the community's organization in the long term by quorum sensing. QS molecules identified in fungi include peptide pheromones, oxylipins, aromatic alcohols (such as tyrosol and farnesol [25]), α1-3 glucans [26], and pantothenic acid [23,27,28]. A number of fungi among Arthoniomycetes also participate in the formation of lichens, and thus do communicate with algaes (see 1.4).…”

Host Immune Defense upon Fungal Infections with Mucorales: Pathogen-Immune Cell Interactions as Drivers of Inflammatory Responses

“…Microenvironmental factors other than cytokines (e.g., oxygen, lipids, glucose, microbial products, or salts) are involved in the differentiation of immune cells, which might impact their capacity to control fungal infections [ 70 , 71 , 72 , 73 , 74 ]. For example, sodium chloride (NaCl) is usually found in peripheral tissues and promotes differentiation of human and murine Th17 cells with anti-inflammatory properties [ 70 , 75 ].…”