ES-62, an immunomodulator secreted by filarial nematodes, exhibits therapeutic potential in mouse models of allergic inflammation, at least in part by inducing the desensitisation of FcεRI-mediated mast cell responses. However, in addition to their pathogenic roles in allergic and autoimmune diseases, mast cells are important in fighting infection, wound healing, and resolving inflammation, reflecting that mast cells exhibit a phenotypic and functional plasticity. We have therefore characterised the differential functional responses to antigen (via FcεRI) and LPS and their modulation by ES-62 of the mature peritoneal-derived mast cells (PDMC; serosal) and those of the connective tissue-like mast cells (CTMC) and the mucosal-like mast cells derived from bone marrow progenitors (BMMC) as a first step to produce disease tissue-targeted therapeutics based on ES-62 action. All three mast cell populations were rendered hyporesponsive by ES-62 and whilst the mechanisms underlying such desensitisation have not been fully delineated, they reflect a downregulation of calcium and PKCα signalling. ES-62 also downregulated MyD88 and PKCδ in mucosal-type BMMC but not PDMC, the additional signals targeted in mucosal-type BMMC likely reflecting that these cells respond to antigen and LPS by degranulation and cytokine secretion whereas PDMC predominantly respond in a degranulation-based manner. 1. Introduction Mast cells are increasingly recognised as playing an important pathogenic role in a variety of allergic and autoimmune diseases [1–4]. However, there is also developing evidence of their participation in tissue repair and resolution of inflammation [5–7], as well as for their exhibiting pathogenic and protective roles in cancer [8, 9]. Such contradictory evidence relating to mast cell function most likely reflects that mast cells, which are haematopoietic cells found in all vascularised organs [10–13], constitute a heterogeneous cell population [14] varying in morphology, function, and location with subpopulations being characterised by their differential protease, eicosanoid, and proteoglycan content [10, 13–17]. Such heterogeneity arises because bone marrow-derived mast cell progenitors [18, 19] arrive in tissue before they are fully matured [20] allowing the different cytokines, hormones, and reactive oxygen and/or nitrogen species produced by various microenvironments to essentially create “custom-made” site-specific mast cells [12–14]. Moreover, the functional response of mast cells depends on the stimuli received [12]; for example, following classical
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