Native and IgE-primed rat peritoneal mast cells exert pro-inflammatory activity and migrate in response to yeast zymosan upon Dectin-1 engagement

Abstract

Mast cells (MCs) play an essential role in host defense, primarily because of their location, their ability to pathogen destruction via several mechanisms, and the pattern recognition receptors they express. Even though most data is available regarding MC activation by various bacteria- or virus-derived molecules, those cells’ activity in response to constituents associated with fungi is not recognized enough. Our research aimed to address whether Saccharomyces cerevisiae-derived zymosan, i.e., β-(1,3)-glucan containing mannan particles, impacts MC activity aspects. Overall, the obtained results indicate that zymosan has the potential to elicit a pro-inflammatory response of rat peritoneal MCs. For the first time ever, we provided evidence that zymosan induces fully mature MC migration, even in the absence of extracellular matrix (ECM) proteins. Moreover, the zymosan-induced migratory response of MCs is almost entirely a result of directional migration, i.e., chemotaxis. We found that zymosan stimulates MCs to degranulate and generate lipid mediators (cysLTs), cytokines (IFN-α, IFN-β, IFN-γ, GM-CSF, TNF), and chemokine (CCL2). Zymosan also upregulated mRNA transcripts for several cytokines/chemokines with pro-inflammatory/immunoregulatory activity. Moreover, we documented that zymosan activates MCs to produce reactive oxygen species (ROS). Lastly, we established that the zymosan-induced MC response is mediated through activation of the Dectin-1 receptor. In general, our results strongly support the notion that MCs contribute to innate antifungal immunity and bring us closer to elucidate their role in host-pathogenic fungi interactions. Besides, provided findings on IgE-sensitized MCs appear to indicate that exposure to fungal zymosan could affect the severity of IgE-dependent disorders, including allergic ones.

Do Mast Cells Contribute to the Antifungal Host Defense?

“…In turn, stimulation with zymosan results in an increase of IL-33 mRNA expression [88] as well as LTB 4 , LTC 4 , IL-1β, and GM-CSF synthesis by CBMCs [35,84]. Moreover, our paper reported that PMCs release cysLTs, IFNs, GM-CSF, TNF, and CCL2 in response to zymosan [83]. It has also been demonstrated that PbPga1 protein, a surface antigen of P. brasiliensis yeast, induces IL-6 release from RBL-2H3 cells [63].…”

“…It has been established that zymosan from S. cerevisiae stimulated ROS and NO generation by murine BMMCs [34,78]. We have recently documented that zymosan and mannan, as well as curdlan, also promote ROS generation by rat PMCs [38,82,83]. Some fungus-associated molecules promote MC chemotactic activity.…”

“…Interestingly, Aspergillus oryzaederived lectin induces the secretion of β-hexosaminidase from RBL-2H3 sensitized with IgE [81]. Furthermore, mannan and/or zymosan from S. cerevisiae stimulates rat PMCs but not CBMCs to degranulate [82][83][84]. In turn, β-glucan derived from Aureobasidium pullulans inhibits the degranulation of both RBL-2H3 and BMMCs without causing cytotoxicity towards these cells [85].…”

“…β-glucans, including zymosan and curdlan, as well as mannan, serve as potent chemoattractants for rat PMCs. Recently, we have shown that these molecules cause migration of rat PMCs, even in the absence of extracellular matrix (ECM) proteins [38,82,83]. It can be therefore stated that MCs accumulate in large numbers at the site of fungal infection.…”

The Emerging Role of Mast Cells in Response to Fungal Infection

“…Dectin-1 can recognize β-glucans and trigger a variety of cellular responses such as phagocytosis and the production of cytokines. Zymosan, a β-glucan derived from yeast of Saccharomyces cerevisiae , for example, induced mature mice peritoneal MCs migration and pro-inflammatory expression via Dectin-1 ( 19 ). Similar results were observed in human cord blood-derived mast cells (CBMCs).…”