Cannabidiol-Dominant Cannabis sativa L. Inflorescence Extract Ameliorates Atopic Dermatitis by Modulating NLRP3 Inflammasome and JAK1/STAT6 Signaling in DNCB-Induced Mice

Source / Quelle: https://www.mdpi.com/2072-6643/18/14/2382

Abstract

Background/Objectives: Atopic dermatitis (AD) is a chronic inflammatory skin disorder requiring sustainable therapeutic alternatives. Cannabis sativa L. is a valuable industrial crop rich in bioactive secondary metabolites; its potential as a standardized functional ingredient for promoting skin health has not yet been fully investigated. This study aimed to evaluate the therapeutic effects of a chemically characterized C. sativa inflorescence ethanol extract (CSE) on AD. Methods: To evaluate the efficacy of CSE, phytochemical profiling was performed using UPLC, and its underlying molecular mechanisms were investigated in a DNCB-induced mouse model. Results: UPLC analysis was employed to establish the phytochemical profile, identifying 15 cannabinoids and quantifying 8 major components. CBDA was the most abundant component, with a content of 261.79 mg/g in the extract. In a DNCB-induced mouse model, CSE significantly reduced mast cell infiltration and serum IgE levels while downregulating Th2-associated cytokines. At the molecular level, CSE inhibited the activation of the MAPK, NLRP3 inflammasome, and JAK1/STAT6 signaling pathways. Crucially, CSE treatment substantially increased the expression of skin barrier proteins, such as filaggrin and involucrin, thereby enhancing skin hydration. Conclusions: These findings suggest CSE as a high-value functional ingredient capable of ameliorating AD by modulating multi-target immune responses. This study provides a robust scientific basis for utilizing standardized C. sativa inflorescence as a potent functional ingredient or a nutraceutical agent for the management of chronic skin inflammatory conditions.

Keywords:

 Cannabis sativa L.; atopic dermatitis; cannabinoid; nutraceuticals; NLRP3 inflammasome

1. Introduction

Cannabis sativa L., a prominent member of the Cannabaceae family, has been recognized for centuries as a versatile and high-value agricultural crop with extensive applications in fiber production and medicinal use. Originating in Central Asia, this species has been widely disseminated and is now cultivated across diverse geographical regions as a sustainable bioresource. The phytochemical diversity of C. sativa, primarily characterized by the concentration of tetrahydrocannabinol (THC), dictates its industrial utility; while low-THC cultivars are favored for agricultural and food production, high-THC varieties are predominantly utilized in pharmaceuticals [1]. Specifically for medical applications, cultivation conditions significantly influence the concentrations of key bioactive compounds, such as cannabinoids and terpenoids [2]. This variability leads to diverse chemical profiles [3]. Currently, C. sativa is utilized across various sectors, ranging from construction materials, textiles, food ingredients, and medical applications [2].

Beyond its industrial versatility, C. sativa serves as a rich natural reservoir of secondary metabolites, exhibiting a wide range of therapeutic effects, including antioxidant, anti-inflammatory, and analgesic activities [4]. These biological properties are largely attributed to its unique phytochemical profile, which comprises over 1000 bioactive compounds [5]. While phytocannabinoids are the most prominent constituents, the plant also contains significant amounts of terpenoids and flavonoids, which contribute to its overall pharmacological synergy [6]. To date, approximately 125 phytocannabinoids have been structurally elucidated [7]. Although THC and cannabidiol (CBD) remain the most extensively studied for their clinical applications, there is a growing paradigm shift in food chemistry toward minor cannabinoids such as cannabigerol (CBG), cannabichromene (CBC), and cannabinol (CBN) [8]. These minor components are garnering significant scientific interest due to their distinct pharmacological properties, suggesting that the comprehensive phytochemical standardization of C. sativa inflorescences is crucial for their successful application in the nutraceutical and functional food industries.

AD is a chronic, relapsing inflammatory skin disease characterized by pruritus, eczematous lesions, and skin barrier dysfunction. It is considered a refractory condition due to its tendency for frequent exacerbations and limited long-term treatment response. Although AD is a common skin disorder in pediatric populations, it remains a challenging condition to fully cure [9]. AD is a multifactorial disease in which genetic, immunological, and environmental factors contribute to its pathogenesis through complex and interrelated mechanisms. Among these, T helper type 2 (Th2) immune responses and skin barrier function play critical roles, and abnormalities in these mechanisms exacerbate skin inflammation and induce severe pruritus [10].

Th2 cytokines, particularly interleukin (IL)-4 and IL-13, serve as pivotal mediators in the pathogenesis of AD. These cytokines drive B cell class switching toward immunoglobulin E (IgE) production and promote eosinophilic inflammation [11]. In addition to amplifying allergic responses, IL-4 and IL-13 disrupt epidermal barrier integrity by downregulating filaggrin and other barrier-associated proteins, thereby perpetuating chronic inflammation and disease severity.

Epidermal barrier abnormalities, including functional defects in filaggrin, are commonly observed pathological features of AD lesions. Defects in filaggrin expression, resulting from genetic mutations or the effects of Th2 cytokines, compromise barrier integrity, leading to increased transepidermal water loss, heightened susceptibility to infection, and subsequent skin dryness and pruritus [12]. Given the chronic and relapsing nature of these barrier defects and immune dysregulation, the utilization of plant-derived bioactive compounds represents a promising strategy for long-term management, owing to their potential for multi-target efficacy and safety.

Previous studies have reported that CBD reduces edema and suppresses inflammation in in vivo models, thereby demonstrating therapeutic effects in AD [13]. Despite these promising findings, the complex synergistic effects of the diverse phytochemicals present in C. sativa extracts remain largely unexplored, and the precise molecular mechanisms underlying their action on the skin barrier and immune signaling are not yet fully elucidated. Since the biological efficacy of plant extracts is intrinsically linked to their phytochemical standardization, a comprehensive investigation into the multi-target effects of whole-plant extracts is essential for their development as reliable therapeutic agents.

In this context, this study aimed to evaluate the therapeutic efficacy of a chemically characterized 70% ethanol extract of C. sativa inflorescence—a variety developed in the Republic of Korea—on 2,4-Dinitrochlorobenzene (DNCB)-induced AD in mice. Furthermore, the underlying chemical-biological interactions were elucidated by analyzing the modulation of the MAPK, NLRP3 inflammasome, and JAK1/STAT6 signaling pathways, alongside the restoration of key skin barrier proteins.

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