IgE-mediated mast cell responses are inhibited by thymol-mediated, activation-induced cell death in skin inflammation

Abstract

Background Mast cells play a critical role in inflammatory skin diseases through releasing pro-inflammatory mediators; however, few therapies directly target these cells. In 1878, the use of topical Thymol, a now recognized potent agonist for Transient Receptor Potential (TRP) channels, was first described to treat eczema and psoriasis. Objective We sought to determine the mechanisms through which thymol may alter skin inflammation. Methods We examined the effect of topical thymol on IgE-dependent responses using a mast cell–dependent passive cutaneous anaphylaxis (PCA) model as well as in vitro cultured mast cells. Results Thymol dose-dependently inhibited PCA when administered topically 24 hours prior to antigen challenge but provoked an ear swelling response directly on application. This direct effect was associated with local mast cell degranulation and was absent in histamine-deficient mice. However, unlike with PCA responses, there was no late phase swelling. In vitro, thymol directly trigged calcium flux in mast cells via TRP-channel activation, along with degranulation and cytokine transcription. However, no cytokine protein was produced. Instead, thymol induced a significant increase in apoptotic cell death that was seen both in vitro and in vivo. Conclusions We propose that the efficacy of thymol in reducing IgE-dependent responses is through promotion of activation-induced apoptotic cell death of mast cells and that this likely explains the clinical benefits observed in early clinical reports.

Thymol, thyme, and other plant sources: Health and potential uses

“…For example, the results of Riella et al () suggested that thymol exhibited anti‐inflammatory activity and wound healing in a paw edema as well as peritonitis rodent models treated with thymol (10, 30, and 100 mg/kg). Using different in vitro and in vivo models, Wechsler et al () have also revealed that thymol promoted an activation‐induced apoptotic death of mast cells, which led to a suppression of subsequent IgE‐dependent responses to antigen. Thus, thymol could be used topically for the ablation of mast cell‐associated skin inflammation disorders (Wechsler et al, ).…”

Humanized mouse model of mast cell–mediated passive cutaneous anaphylaxis and passive systemic anaphylaxis

“…PEC of NSG-SGM3 BLT mice were cultured to enrich for human mast cells and tested for calcium flux as described (13) . Briefly, mast cells were treated with 100 ng/mL chIgE-anti-NP overnight.…”

Thymol produces an antidepressant-like effect in a chronic unpredictable mild stress model of depression in mice

“…Data from clinical and preclinical studies suggested that inflammatory cytokines increased in depressed patients and in animal models of depression, and the inhibition of the inflammatory processes might ameliorate their depressive symptoms [40]. Thymol exhibited strong anti-inflammatory activities in the models of osteoarthritis [20], asthma [21], skin inflammation [41], ear edema [42], and peritonitis [43] etc. It has been reported to attenuate inflammation through downregulating the expressions of proinflammatory cytokines, such as TNF-␣ [19,30,44], IL-1␤ [19], and IL-6 [19,44].…”