Mast cells and inflammation.

Mast cells are well known for their role in allergic and anaphylactic reactions, as well as their involvement in acquired and innate immunity. Increasing evidence now implicates mast cells in inflammatory diseases where they are activated by non-allergic triggers, such as neuropeptides and cytokines, often exerting synergistic effects as in the case of IL-33 and neurotensin. Mast cells can also release pro-inflammatory mediators selectively without degranulation. In particular, IL-1 induces selective release of IL-6, while corticotropin-releasing hormone secreted under stress induces the release of vascular endothelial growth factor. Many inflammatory diseases involve mast cells in cross-talk with T cells, such as atopic dermatitis, psoriasis and multiple sclerosis, which all worsen by stress. How mast cell differential responses are regulated is still unresolved. Preliminary evidence suggests that mitochondrial function and dynamics control mast cell degranulation, but not selective release. Recent findings also indicate that mast cells have immunomodulatory properties. Understanding selective release of mediators could explain how mast cells participate in numerous diverse biologic processes, and how they exert both immunostimulatory and immunosuppressive actions. Unraveling selective mast cell secretion could also help develop unique mast cell inhibitors with novel therapeutic applications. This article is part of a Special Issue entitled: Mast cells in inflammation.

Childhood- and later-onset vitiligo have diverse epidemiologic and clinical characteristics.

BACKGROUND: Vitiligo onset during childhood is common. There are limited data regarding childhood-onset vitiligo. OBJECTIVE: We sought to provide an epidemiologic and clinical comparison between childhood- and later-onset vitiligo. METHODS: Two groups of patients were included in this cross-sectional study. Consecutive patients examined at the Vitiligo Clinic of Andreas Sygros Hospital for Skin and Venereal Diseases, Athens, Greece, from January 2005 to December 2009 with a disease onset before the age of 12 years were included in the childhood-onset group. The later-onset group included randomly selected patients who were examined at the same period and had a disease onset after the age of 12 years. After clinical examination, a standardized questionnaire was completed for each patient. RESULTS: In all, 126 patients were included in the childhood-onset and 107 patients in the later-onset group. Childhood-onset vitiligo: (1) involved different sites at initial presentation, (2) included more cases of segmental type, and (3) was characterized by a higher prevalence of allergic diseases and a lower prevalence of thyroid diseases. Longer duration of disease and a positive family history of thyroid disease were associated with the presence of thyroid disease only in the childhood-onset group. In the later-onset group, only female sex was associated with the presence of thyroid disease. LIMITATIONS: The study was conducted in a hospital specializing in skin diseases and a selection bias toward more severe vitiligo cases is possible. CONCLUSIONS: Childhood-onset vitiligo had distinct epidemiologic and clinical characteristics, compared with later-onset disease.

Human mast cell degranulation and preformed TNF secretion require mitochondrial translocation to exocytosis sites: relevance to atopic dermatitis.

BACKGROUND: Mast cells derive from hematopoietic cell precursors and participate in tissue allergic, immune, and inflammatory processes. They secrete many mediators, including preformed TNF, in response to allergic, neuropeptide, and environmental triggers. However, regulation of mast cell degranulation is not well understood. OBJECTIVE: We investigated the role of mitochondrial dynamics in degranulation of human cultured mast cells. METHODS: Human umbilical cord blood-derived mast cells (hCBMCs) and Laboratory of Allergic Diseases 2 (LAD2) mast cells were examined by confocal and differential interference contrast microscopy during activation by IgE/antigen and substance P (SP). Mast cells in control and atopic dermatitis (AD) skin were evaluated by transmission electron microscopy. LAD2 cells were pretreated with mitochondrial division inhibitor, a dynamin-related protein 1 (Drp1) inhibitor, and small interfering RNA for Drp1, which is necessary for mitochondrial fission and translocation. Calcineurin and Drp1 gene expression was analyzed in stimulated LAD2 cells and AD skin biopsies. RESULTS: Stimulation of hCBMCs with IgE/antigen or LAD2 cells with SP leads to rapid (30 minutes) secretion of preformed TNF. Degranulation is accompanied by mitochondrial translocation from a perinuclear location to exocytosis sites. Extracellular calcium depletion prevents these effects, indicating calcium requirement. The calcium-dependent calcineurin and Drp1 are activated 30 minutes after SP stimulation. Reduction of Drp1 activity by mitochondrial division inhibitor and decrease of Drp1 expression using small interfering RNA inhibit mitochondrial translocation, degranulation, and TNF secretion. Mitochondrial translocation is also evident by transmission electron microscopy in skin mast cells from AD biopsies, in which gene expression of calcineurin, Drp1, and SP is higher than in normal skin. CONCLUSION: Human mast cell degranulation requires mitochondrial dynamics, also implicated in AD.

Substance P (SP) induces expression of functional corticotropin-releasing hormone receptor-1 (CRHR-1) in human mast cells.

Corticotropin-releasing hormone (CRH) is secreted under stress and regulates the hypothalamic-pituitary-adrenal axis. However, CRH is also secreted outside the brain where it exerts proinflammatory effects through activation of mast cells, which are increasingly implicated in immunity and inflammation. Substance P (SP) is also involved in inflammatory diseases. Human LAD2 leukemic mast cells express only CRHR-1 mRNA weakly. Treatment of LAD2 cells with SP (0.5-2 µM) for 6 hours significantly increases corticotropin-releasing hormone receptor-1 (CRHR-1) mRNA and protein expression. Addition of CRH (1 µM) to LAD2 cells, which are "primed" with SP for 48 hours and then washed, induces synthesis and release of IL-8, tumor necrosis factor (TNF), and vascular endothelial growth factor (VEGF) 24 hours later. These effects are blocked by pretreatment with an NK-1 receptor antagonist. Treatment of LAD2 cells with CRH (1 µM) for 6 hours induces gene expression of NK-1 as compared with controls. However, repeated stimulation of mast cells with CRH (1 µM) leads to downregulation of CRHR-1 and upregulation in NK-1 gene expression. These results indicate that SP can stimulate mast cells and also increase expression of functional CRHR-1, whereas CRH induces NK-1 gene expression. These results may explain CRHR-1 and NK-1 expression in lesional skin of psoriatic patients.