Abstract
BackgroundAtopic dermatitis (AD) is a chronic inflammatory skin disease characterized by highly pruritic eczematous lesions that are commonly treated with topical corticosteroids and calcineurin inhibitors. Side-effects and safety concerns associated with these agents restrict their use, and new, safe treatment options are therefore needed. Recent reports suggest that serotonin, i.e. 5-hydroxytryptamine (5-HT) and the 5-HT2 receptor family may contribute to inflammation and pruritus in the skin. The objective of this particular study was to investigate the 5HT2B receptor antagonist AM1030 with respect to its anti-inflammatory profile and potential.MethodsAM1030 was tested in a set of distinct human and rodent in vitro and in vivo models, differing with respect to e.g. T cell involvement, triggering stimulus, main read-outs and route of drug administration. The in vitro systems used were staphylococcal enterotoxin A (SEA)-stimulated human peripheral blood mononuclear cells, lipopolysaccharide (LPS)-stimulated human primary monocytes, LPS-stimulated human THP-1 monocytes and LPS-stimulated mouse primary macrophages. The in vivo systems used were LPS- and SEA-induced cytokine production in the mouse, antigen-induced arthritis in the rat, glucose-6-phosphate isomerase-induced arthritis in the mouse and delayed-type hypersensitivity reaction in the mouse. In addition, different cell populations were analyzed with respect to their expression of the 5-HT2B receptor at the mRNA level.ResultsAM1030 significantly reduced both T cell-dependent and T cell-independent inflammatory responses, in vivo and in vitro. Due to the low or absent expression of the 5-HT2B receptor on T cell populations, the influence of AM1030 in T cell-dependent systems is suggested to be mediated via an indirect effect involving antigen-presenting cell types, such as monocytes and macrophages.ConclusionBased on the wide range of model systems used in this study, differing e.g. with respect to species, T cell involvement, triggering stimuli, route of drug administration and read-outs, our results suggest a broad anti-inflammatory effect of AM1030 and identify the 5-HT2B receptor as a promising future target for anti-inflammatory intervention, e.g. in AD.
Highlights
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by highly pruritic eczematous lesions that are commonly treated with topical corticosteroids and calcineurin inhibitors
AM1030 reduces staphylococcal enterotoxin A (SEA)-induced cytokine responses in human peripheral blood mononuclear cells (PBMC) Staphylococcal enterotoxin A (SEA) is a T cell superantigen frequently expressed by S. aureus strains colonizing AD skin [8, 9]
In an in vitro model based on PBMCs isolated from healthy blood donors, SEA was used to mimic the process of antigen presentation and to thereby induce cytokine production from both antigen-presenting cells (APCs; e.g. macrophages) and T cells [32]
Summary
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by highly pruritic eczematous lesions that are commonly treated with topical corticosteroids and calcineurin inhibitors. Recent reports suggest that serotonin, i.e. 5-hydroxytryptamine (5-HT) and the 5-HT2 receptor family may contribute to inflammation and pruritus in the skin The objective of this particular study was to investigate the 5HT2B receptor antagonist AM1030 with respect to its anti-inflammatory profile and potential. The AD lesion is characterized by an immune response involving several T cell subsets, with a significant contribution of the Th1 subset [3, 6, 7]. This shift in T cell subset predominance may be caused by an increased exposure of the immune system to non-allergen triggers, including microbial products [6]. Skin colonization with superantigen-producing strains of S. aureus is very common in AD patients [6, 8, 9]
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