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Mast cells (MCs) are the principal effector cells of IgE-mediated allergy. IL-33 is released by resident skin cells as alarmin upon tissue damage or allergen contact. Owing to their pronounced receptor expression, MCs are important targets of IL-33 action, but consequences for skin MCs are ill-defined, especially upon chronic exposure to IL-33. Mimicking the inflammatory milieu of skin disorders, we found that persistent exposure to IL-33 (over a 5-week period) strengthened skin MC numbers through accelerated cell-cycle progression and restriction of apoptosis. Conversely, IL-33 attenuated degranulation and FcεRI expression, potentially as a feedback to chronic "alarmin" exposure. Interestingly, the negative impact on histamine release was counterbalanced by amplified histamine production. Considering the clinical significance of histamine and scarce information on its regulation, we explored the molecular underpinnings. IL-33 induced swift phosphorylation of p38 and JNK (but not of ERK1/2 or AKT), and stimulated histidine decarboxylase expression. Combining pharmacological inhibition and kinase elimination by Accell-facilitated RNA interference in skin MCs revealed a p38-dependent, but JNK-independent mechanism. Collectively, IL-33 exerts multifaceted effects on cutaneous MCs at a post-maturation stage. The IL-33-skin MC axis may contribute to and balance inflammation in chronic skin disorders., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Proteinase-activated receptor-2 (PAR2) belongs to a new G protein-coupled receptor subfamily activated by serine proteinases. PAR2 has been demonstrated to play a role during inflammation and immune response in different tissues including the skin. We examined whether PAR2 is functionally expressed by cutaneous human primary skin mast cells (HPMC) and the human mast cell line 1 (HMC-1). Reverse transcription-polymerase chain reaction and FACS analysis show expression of PAR2 both at the RNA and protein level. HPMCs and HMC-1 also express PAR1, PAR3, and PAR4. Ca-mobilization studies demonstrate functional PAR2 expressed by human skin mast cells, as shown by natural and synthetic PAR2 agonists. PAR2 agonists induced histamine release from HPMC indicating a role of PAR2 in regulating inflammatory and immune responses by skin mast cells. Double-immunofluorescence staining reveals colocalization of PAR2 with tryptase in the majority of human skin mast cells. In conclusion, trypsin and tryptase as well as specific agonists for PAR2 were able to induce Ca2+ mobilization in HPMCs, and agonists of PAR2 induce the release of histamine from these cells. Thus, PAR2 may be an important regulator of skin mast cell function during cutaneous inflammation and hypersensitivity.

Mast cells generate and release histamine during anaphylactic reactions, and there is pharmacological evidence that histamine regulates this process via specific receptors. Therefore, we examined human leukemic (HMC-1) and normal skin mast cells for the expression of all four currently known histamine receptors. Both cell types expressed H2 and H4 receptors at mRNA and protein levels, whereas H3 receptor specific mRNA and receptor protein was undetectable. Similarly, immunohistochemistry of cutaneous tissue showed an absence of H3 receptor in these cells. Despite transcription of mRNA, H1 receptor protein was only moderately expressed in HMC-1 cells and was virtually absent in skin mast cells. Furthermore, only H1, H2, and H4 receptors were detectable by Western blot analysis of HMC-1 cells. Radiolabeled histamine binding was strongly inhibited only by H2 (ranitidine)- and H3/H4 (FUB 108)-specific antagonists. Histamine-induced increase of cAMP was inhibited by the H2 receptor antagonist famotidine, whereas induction of IP3 was not observed, making signaling via the H1 receptor unlikely. These data show that human mast cells constitutively express primarily H2 and H4 receptors and that H2 receptors are functionally linked to cellular processes. They provide new insights into the mechanisms that govern auto- and paracrine histamine-induced mast cell functions. [ABSTRACT FROM AUTHOR]

As mast cells have been implicated in cutaneous repair processes, we have examined the ability of human mast cells to produce important epithelial and fibroblast growth factors or to stimulate the production of such factors in dermal fibroblasts. Isolated, highly purified human dermal mast cells and human leukemic mast cells were examined for mRNA and partly also for protein expression of these molecules as such or after preincubation with interleukin-4, stem cell factor, or with phorbol myristate acetate. In addition, mast cells were studied for their ability to induce fibroblast growth factor 2 and fibroblast growth factor 7 secretion from dermal fibroblasts. Both dermal and leukemic mast cells expressed fibroblast growth factor 2, fibroblast growth factor 7, and heparin-binding epidermal growth factor, but not hepatocyte growth factor at mRNA level, and dermal mast cells expressed fibroblast growth factor 10 in addition. At protein level, spontaneous fibroblast growth factor 2 secretion was noted that was markedly enhanced by phorbol myristate acetate, whereas no fibroblast growth factor 7 protein was detected under these conditions. Instead, human mast cell-1 supernatants induced enhanced fibroblast growth factor 7 secretion from dermal fibroblasts, with phorbol-myristate-acetate-stimulated supernatants being more effective. This effect could be reproduced with histamine and was H1-receptor mediated. Tryptase was ineffective but stimulated instead fibroblast growth factor 2 secretion from fibroblasts. These data demonstrate for the first time the ability of mast cells to express and/or secrete several growth factors of the fibroblast growth factor family as well as heparin-binding epidermal growth factor directly or indirectly via stimulation of fibroblasts, underlining the potentially pivotal role of these cells during human tissue repair and homeostasis. [ABSTRACT FROM AUTHOR]