Topical treatment with mastic (resin from Pistacia lentiscus) elicits anti-inflammatory and anti-pruritic responses by modulating keratinocyte activation in a mouse model of allergic dermatitis

Abstract

Background

As the number of patients with skin allergies, including atopic dermatitis, has increased rapidly, therapeutic options such as anti-IL-31 antibody and Janus kinase inhibitor have been developed recently. However, many concerns remain regarding the adverse effects and cost of these drugs; therefore, development of supplements that could support the effect of therapeutic agents is always required.

Purpose

The aim of this study was to develop preventive and supportive options for skin allergies by focusing on a natural product called “Mastic”. Methods: Initially, the anti-inflammatory and anti-pruritic responses of 3% and 30% Mastic topical treatment were investigated in a mouse model of allergic contact dermatitis, generated by topical application of toluene-2,4-diisocyanate (TDI), a hapten that induces type 2 helper T cells. After itch behaviour and ear-swelling response were monitored, serum, auricular lymph nodes, and skin tissues were collected to analyse immunocyte differentiation, cytokine determination, and histological changes.

Results

Our findings indicated that topical treatment with mastic significantly ameliorated ear swelling, itch behaviour, immunocyte infiltration, and cytokine production. Histological evaluation confirmed the occurrence of anti-inflammatory responses. The anti-inflammatory and anti-pruritic effects of topical treatment with mastic (3% and 5%) were further confirmed in a mouse model of atopic dermatitis which was generated by topical application of TDI in NC/Nga mice. Thickness of the back skin, AD score, transepidermal water loss (TEWL), and itch behaviour were measured weekly, and immunocyte differentiation, cytokine determination, and histological changes were also analysed. Mastic treatment significantly attenuated the skin thickness, AD score, TEWL, and itch behaviour. Corroborated reduction was observed in the numbers of T cells and IgE-B cells, as well as in pro-inflammatory cytokine production. The reproducibility of the effects of mastic was confirmed with 1% mastic ointment in a setting similar to the AD mouse model. In vitro evaluation of keratinocytes indicated that mastic pre-exposure induced a significant dose-dependent decrease in cytokine production.

Conclusion

Our findings thus demonstrate that topical treatment with mastic significantly ameliorate inflammatory and pruritic responses in a mouse model of allergic dermatitis.

Introduction

Mastic is a natural resin obtained from the stem and leaves of the Pistacia lentiscus tree, which exists only on the Greek island of Chios (Amerikanou et al., 2021; Papada and Kaliora, 2019). In the 10^th century, tourists visiting Chios discovered that Chios produced mastic. Although mastic can be produced outside Chios, the process involving the sap dripping and falling is only conducted in Chios. Over time, the sap turns into a yellow mass, sometimes called “tears of Christ” because its shape resembles tears (Amerikanou et al., 2021; Papada and Kaliora, 2019). In Greece, chewing mastic has long been considered to prevent periodontal disease. Previous studies have shown that mastic extract significantly inhibits the growth of periodontal pathogens, and has beneficial effects on cell viability; thus, it could be considered an alternative antibacterial agent for preventing periodontal disease (Carrol et al., 2020; Koychev et al., 2017). Besides its anti-bacterial effects, the anti-inflammatory effects of mastic have also been demonstrated in several reports. Papalois et al. (2012) demonstrated that mastic treatment downregulated the levels of IL-8 and NF-κB p65 in vitro. Triantafyllou et al. (2011) also indicated that the anti-inflammatory activity of Chios mastic gum was associated with the inhibition of TNF-α-induced oxidative stress. In addition, anti-inflammatory effects of plant-derived components such as green tea extract and glycyrrhizic acid have been used for centuries all over the world (Chu et al., 2017; Hasan et al., 2021). However, the anti-inflammatory effects of Chios mastic in vivo, using actual models of inflammatory diseases are not fully understood. Therefore, the initial aim of this study was to investigate the anti-inflammatory effects of Chios mastic in vivo using a mouse model of allergic dermatitis.

Dermatitis is a skin inflammatory condition that occurs in many forms including itching, eczema, dry red skin, rash, and swelling (Williams, 2005). Among these types of cutaneous allergy, atopic dermatitis (AD) is one of the most frequent forms of dermatitis in infants (Rizk et al., 2019). AD is a common skin disease in dogs and cats. Its clinical, immunological, histological, and pathological features are highly similar between dogs and humans; thus, canine AD has been suggested as an animal model for human AD (Mineshige et al., 2018). There are several therapeutic options for AD including oral supplements such as omega-3 fatty acids and lactobacilli; however topical treatment options are still limited, even though topical treatment is a more popular method to improve inflammatory symptoms. Therefore, this study aimed to introduce Chios mastic as a novel supplemental option for skin allergy. We investigated the anti-inflammatory and anti-itch responses of topical treatment with mastic ointment in a mouse model of allergic contact dermatitis (ACD) and AD.