Rutaecarpine ameliorates imiquimod-induced psoriasis-like dermatitis in mice associated with alterations in the gut microbiota

Abstract

Psoriasis is accepted as a chronic, inflammatory, immune-mediated skin disease triggered by complex environmental and genetic factors. For a long time, disease recurrence, drug rejection, and high treatment costs have remained enormous challenges and burdens to patients and clinicians. Natural products with effective immunomodulatory and anti-inflammatory activities from medicinal plants have the potential to combat psoriasis and complications. Herein, an imiquimod (IMQ)-induced psoriasis-like dermatitis model is established in mice. The model mice are treated with 1% rutaecarpine (RUT) (external use) or the oral administration of RUT at different concentrations. Furthermore, high-throughput 16S rRNA gene sequencing is applied to analyze the changes in the diversity and composition of the gut microbiota. Based on the observation of mouse dorsal skin changes, RUT can protect against inflammation to improve psoriasis-like skin damage in mice. Additionally, RUT could suppress the expression levels of proinflammatory cytokines (IL-23, IL-17A, IL-22, IL-6, and IFN-α) within skin tissue samples. Concerning gut microbiota, we find obvious variations within the composition of gut microflora between IMQ-induced psoriasis mice and RUT-treated psoriasis mice. RUT effectively mediates the recovery of gut microbiota in mice induced by IMQ application. Psoriasis is linked to the production of several inflammatory cytokines and gut microbiome alterations. This research shows that RUT might restore gut microbiota homeostasis, reduce inflammatory cytokine production, and ameliorate psoriasis symptoms. In conclusion, the gut microbiota might be a therapeutic target or biomarker for psoriasis that aids in clinical diagnosis and therapy.

1. Introduction

Psoriasis is accepted as a chronic, inflammatory, immune-mediated skin disease triggered by complex environmental and genetic factors. It is estimated to affect at least 200 million people globally [1]. Worse still, psoriasis greatly promotes the incidence rate of psoriatic arthritis (PsA), cardiovascular disease (CVD), diabetes, obesity, depression, nonalcoholic fatty liver disease (NAFLD), and even carcinoma [2–4]. Psoriasis is characterized by raised red scaly plaques caused by excessive keratinocyte proliferation and abnormal keratinocyte differentiation [5]. A previous study highlighted a strong link between excessive keratinocyte proliferation and increased infiltration of inflammatory cells. Specifically, this includes T lymphocytes, macrophages, neutrophils, and dendritic cells (DCs) [6]. This whole process is intrinsically driven by inflammatory factors, including tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-17A, IL-22, IL-23, and IL-1β [7,8]. Currently, psoriasis can be treated primarily through topical corticoids, vitamin D analogs, phototherapy, local treatment, and systemic drug treatment [5,9]. However, these therapeutic methods may be accompanied by disease recurrence, drug rejection, and high costs [10]. Therefore, it is of great urgency to explore safer, cheaper, and more effective natural products with effective immunoregulatory and anti-inflammatory activities from medicinal plants to battle psoriasis and associated consequences.

Rutaecarpine (RUT), an important bioactive alkaloid isolated from Evodia rutaecarpa, is a versatile natural Chinese herbal medicine [11]. RUT shows extensive pharmacological application in the improvement and treatment of inflammation, hyperlipidemia, immune response, allergic reactions, various cardiovascular and cerebrovascular diseases, metabolic diseases, and even cancer [12,13]. It has been shown that RUT intrinsically has anti-injury biological characteristics, which can help to inhibit inflammatory cell infiltration and improve inflammation and tissue proliferation [14–16]. Evidently, RUT can reduce inflammatory reactions by inhibiting NF-κB transcription activity in bacterial lipoteichoic acid (LTA)-induced macrophages [17]. RUT can alleviate immune metabolism-related diseases (including atopic dermatitis and rhinitis) by inhibiting the biosynthesis of inflammatory factors (TNF-α and IL-4) within immunoglobulin E (IgE)-antigen complex-induced RBL2H3 cells [18]. Additionally, we have previously reported that RUT cream can reduce the release of plasmacytoid dendritic cells (pDC)- and Th17-related factors through the NF-κB and TLR7 pathways, thereby reducing inflammation in serum and skin lesions and improving psoriatic dermatitis in mice [19].

Recent studies on psoriasis-related microbiota have revealed a tight link between the intestinal microbiota and skin. The alterations within the gut microbiota composition facilitate the reproduction of bacteria, thus driving psoriasis progression [20,21]. Numerous studies have shown ...