Mannan activates tissue native and IgE-sensitized mast cells to proinflammatory response and chemotaxis in TLR4-dependent manner

Abstract

Mast cells take part in host defense against microorganisms as they are numerous at the portal of infection, exert several essential mechanisms of pathogen destruction, and they express pattern recognition receptors. Accumulating evidence indicates that these cells are involved in the control and clearance of bacterial, viral, or parasitic infections, but much less is known about their contribution in defense against fungi. The study was aimed to establish whether mannan, which comprises an outermost layer and major structural constituent of the fungal cell wall, may directly stimulate tissue mast cells to the antifungal response. Our findings indicate that mannan activates mast cells isolated from the rat peritoneal cavity to initiate the proinflammatory response.We found that mannan stimulates mast cells to release histamine and to generate cysteinyl leukotrienes, cytokines (IFN-, GM-CSF, TNF), and chemokines (CCL2, CCL3). It also increased the mRNA expression of various cytokines/chemokines. We also documented that mannan strongly activates mast cells to generate reactive oxygen species and serves as a potent chemoattractant for these cells. Furthermore, we established that mannan-induced activity of mast cells is mediated via TLR4 with the involvement of the spleen tyrosine kinase molecule. Taking together, our results clearly support the idea that mast cells act as sentinel cells and crucially determine the course of the immune response during fungal infection. Additionally, presented data on IgE-coated mast cells suggest that exposure to fungal mannan could influence the severity of IgE-dependent diseases, including allergic ones.

Responses of Mast Cells to Pathogens: Beneficial and Detrimental Roles

“…Recently, the antifungal response of MCs through TLR4 receptor was demonstrated. Rat peritoneal MCs stimulated with mannan released histamine and produced cysLTs, ROS and pro-inflammatory cytokines and chemokines, such as IFN-γ, GM-CSF, TNF-α, CCL2/MCP-1 and CCL3, via TLR4 and dependent on MyD88, TRIF and Syk ( 268 ). Mannan also increased the gene expression of different immunoregulatory and pro-inflammatory cytokines and the chemoattraction of MCs.…”

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

“…It was documented that βglucan and mannan derived from Candida albicans induced RBL-2H3 cell degranulation and β-hexosaminidase secretion [61]. Also, our recent evidence indicates that mannan obtained from S. cerevisiae activated peritoneal MCs to degranulate and generate several pro-inflammatory/immunoregulatory mediators and ROS as well as serve as a potent chemoattractant for these cells [58]. In contrast, β-(1,3-1,6)-glucan isolated from Aureobasidium pullulans inhibited the degranulation of both BMMCs and RBL-2H3 cells [62].…”

“…Selander et al [57] revealed that Malassezia sympodialis extract enhanced IL-6 production by IgE-sensitized BMMCs. We have recently found that also mannan from S. cerevisiae strengthened some aspects of IgE-sensitized MC activity [58]. Thus, in the presented paper, we wished to determine if priming of MCs with IgE may alter their responsiveness to zymosan.…”

The Emerging Role of Mast Cells in Response to Fungal Infection

“…Compared with bone marrow-derived MCs (BMMCs) from wild type mice C57BL/6, a decrease in C. albicans phagocytosis and nitric oxide (NO) production were detected in TLR2 -/- mice ( 16 ). Whereas mannan, extracted from Saccharomyces cerevisiae , directly activates murine CTMC to initiate the proinflammatory response via TLR4 ( 17 ). When pretreated with TAK242, a small-molecule-specific inhibitor of TLR4 signaling, CTMC significantly decreased the generation of cysLT and reactive oxygen species (ROS) as compared to nontreated MCs in response to mannan ( 17 ).…”

“…Whereas mannan, extracted from Saccharomyces cerevisiae , directly activates murine CTMC to initiate the proinflammatory response via TLR4 ( 17 ). When pretreated with TAK242, a small-molecule-specific inhibitor of TLR4 signaling, CTMC significantly decreased the generation of cysLT and reactive oxygen species (ROS) as compared to nontreated MCs in response to mannan ( 17 ). In summary, TLR2 and TLR4 are the main members of TLRs on MCs with potential to bind different PAMPs on the surface of fungi and induce subsequent host immune response.…”