Abstract
Mast cells and their mediators play a role in the control of homeostasis and in the pathogenesis of several disorders. The concept of rodent mast cell heterogeneity, initially established in the mid-1960s has been extended in humans. Human mast cells isolated and purified from different anatomic sites can be activated via aggregation of cell surface high affinity IgE receptors (FcεRI) by antigens, superantigens, anti-IgE, and anti-FcεRI. MAS-related G protein-coupled receptor-X2 (MRGPRX2) is expressed at high level in human skin mast cells (MCs) (HSMCs), synovial MCs (HSyMCs), but not in lung MCs (HLMCs). MRGPX2 can be activated by neuropeptide substance P, several opioids, cationic drugs, and 48/80. Substance P (5 × 10−7 M – 5 × 10−6 M) induced histamine and tryptase release from HSMCs and to a lesser extent from HSyMCs, but not from HLMCs and human cardiac MCs (HHMCs). Morphine (10−5 M – 3 × 10−4 M) selectively induced histamine and tryptase release from HSMCs, but not from HLMCs and HHMCs. SP and morphine were incomplete secretagogues because they did not induce the de novo synthesis of arachidonic acid metabolites from human mast cells. In the same experiments anti-IgE (3 μg/ml) induced the release of histamine and tryptase and the de novo synthesis of prostaglandin D2 (PGD2) from HLMCs, HHMCs, HSyMCs, and HSMCs. By contrast, anti-IgE induced the production of leukotriene C4 (LTC4) from HLMCs, HHMCs, HSyMCs, but not from HSMCs. These results are compatible with the heterogeneous expression and function of MRGPRX2 receptor on primary human mast cells isolated from different anatomic sites.
Highlights
Mast cells arise from stem cell-derived human mast cell progenitors in the bone marrow, circulate and complete their maturation in all vascularized tissues (Galli, 2016; Olivera et al, 2018)
Activation of mast cells isolated from human lung (HLMCs) by antigens, anti-IgE and superantigens leads to arachidonic acid metabolism through both the cyclooxygenase and the 5lipoxygenase pathway (Schulman et al, 1982; de Paulis et al, 1991; Stellato et al, 1992a), whereas HSMCs only synthesize prostaglandin D2 (PGD2) (Benyon et al, 1987; Stellato et al, 1992b)
As previously reported (Peachell et al, 1988; de Paulis et al, 1996; Genovese et al, 2000; Varricchi et al, 2019), exposure of mast cells isolated from different anatomic sites to anti-IgE (10−1 to 3 μg/ml) resulted in a dose dependent release of histamine
Summary
Mast cells arise from stem cell-derived human mast cell progenitors in the bone marrow, circulate and complete their maturation in all vascularized tissues (Galli, 2016; Olivera et al, 2018). Activation of mast cells isolated from human lung (HLMCs) by antigens, anti-IgE and superantigens leads to arachidonic acid metabolism through both the cyclooxygenase (prostaglandin D2, PGD2) and the 5lipoxygenase pathway (peptide leukotriene C4, LTC4) (Schulman et al, 1982; de Paulis et al, 1991; Stellato et al, 1992a), whereas HSMCs only synthesize PGD2 (Benyon et al, 1987; Stellato et al, 1992b) Based on their protease composition, two types of human mast cells have been proposed: tryptase+ chymase+ cells (MTC), and tryptase+ chymase− (MT), being the prototypes (Schwartz et al, 1987). Recent evidence indicates that each of the two mast cell subsets originates from different precursors through several waves of mast cell differentiation, and that they display distinct surface receptors and mediators (Gentek et al, 2018; Li et al, 2018)
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