Differential TLR-Induced cytokine production by human mast cells is amplified by Fce{open}RI triggering

Abstract

Background: Mast cells are mainly present in strategic locations, where they may have a role in defence against parasites and bacteria. These pathogens can be recognized by mast cells via Toll-like receptors (TLR). Allergic symptoms are often increased in the presence of pathogens at the site of allergen exposure, but it is unknown which cytokines can mediate such an effect. Objective: To study whether an interaction between IgE- and TLR-mediated activation of human mast cells can contribute to exacerbated inflammatory responses. Methods: Peripheral blood-derived mast cells were stimulated with TLR ligands, in the presence or absence of anti-IgE triggering, after which degranulation was measured using flow cytometry and cytokine production was evaluated by multiplex assays, and ELISA. For evaluation of allergen-specific responses, mast cells were sensitized with serum of allergic individuals or controls, after which they were stimulated using allergens in combination with TLR ligands. Results: Simultaneous triggering of mast cells via IgE and TLR ligands greatly enhanced cytokine production but not IgE-induced degranulation. Different TLR ligands specifically enhanced the differential production of cytokines in conjunction with FcεRI triggering. Importantly, only TLR-4 and TLR-6 were able to induce robust production of IL-13, an important molecule in allergic reactions. Conclusions & Clinical Relevance: These results indicate that the simultaneous presence of pathogen- or danger-associated signals and FcεRI triggering via specific IgE can significantly modify mast cell-mediated allergic reactions via synergistic production of cytokines and inflammatory mediators and provide an explanation of augmented allergic symptoms during infection.