Psoriasis is a chronic inflammatory skin disease mediated by the immune system. It is characterized by the abnormal proliferation of keratinocytes, infiltration of immune cells, and proliferation of dermal blood vessels [1]. The disease affects approximately 125 million people worldwide, and its prevalence is increasing annually. This imposes a significant economic burden on both society and the families of patients [2]. Psoriasis is frequently associated with multi-organ complications, including psoriatic arthritis, non-alcoholic fatty liver disease, Crohn's disease, lymphoma, cardiovascular disease, and obesity [3], [4]. It’s also a chronic condition that can easily recur and substantially affect the physical and mental health of patients. The disease and its complications can increase the risk of anxiety, depression, and suicide. It is important to provide proper care and support to patients with psoriasis [5]. The causes of psoriasis development are not yet fully understood, and the disease cannot be cured completely either. While methotrexate, cyclosporine, immunosuppressants, and other therapies have shown significant clinical efficacy, but their long-term use can result in adverse reactions and side effects [6]. Thus, it is imperative to investigate thoroughly the pathogenesis of psoriasis and develop safer and more effective new treatments to alleviate the health burden of this disease.

The development of psoriasis is a complicated process involving genetic and environmental factors, as well as immune dysfunctions [7]. It is commonly recognized as an immune-mediated disorder and various immune cells and inflammatory cytokines form a complex inflammatory response network that collectively leads to the development of psoriasis. During the early stages of illness, environmental and infectious factors harm keratinocytes, leading to the release of nucleic acids and antimicrobial peptides. These activate innate immune cells, such as plasmacytoid dendritic cells and macrophages, to produce and release interferon (IFN)-γ and tumor necrosis factor (TNF)-α, which activate myeloid dendritic cells to release cytokines such as TNF-α, interleukin (IL)-12, and IL-23, which prompt differentiation of the initial T lymphocytes into Th1, Th17, and Th22 lymphocytes [8], [9]. Activated T lymphocytes release inflammatory cytokines such as IL-17A, TNF-α, IFN-γ, and IL-22, which promote the abnormal proliferation of keratinocytes. In addition, keratinocytes can produce vascular endothelial growth factor, TNF-α, antimicrobial peptides, IL-8, and other cytokines to further activate dendritic cells, forming a malignant inflammatory cycle that leads to plaque residue and deterioration in the chronic phase of psoriasis [10].

Although psoriasis has been positioned as a Th17- mediated inflammatory disease, macrophages are also demonstrated to play a crucial role in the pathogenesis of psoriasis, including production of inflammatory factors, antigen presentation, and phagocytosis of pathogenic microorganisms. Studies have shown that reducing the number of macrophages can effectively improve psoriasis inflammation and reduce the levels of Th1 cytokines, such as IL-1α, IL-6, IL-23, and TNF-α, to normal levels [11], [12]. In the imiquimod (IMQ)-induced psoriasis mouse model, the expression of M1 macrophage-associated factors, including IL-1β, IL-6, TNF-α, and inducible nitric oxide synthase (iNOS), is substantially elevated. PSORI-CM02, a Chinese herb, inhibits M1 macrophages and promotes the expression of M2 macrophage cytokines, thereby improving psoriasis development [13]. Therefore, inhibiting macrophage differentiation and decreasing the number of macrophages could effectively alleviate the development of psoriasis.

In recent years, extensive studies on herbal medicines demonstrate that many herbal monomers have beneficial palliative effects on psoriasis. In addition, natural products are the reasonable choices to develop therapies with minor or no side effects. Cornuside (C24H30O14) is a natural iridoid glycoside isolated from the fruits of Cornus officinalis Sieb. et Zucc. (source: http://www.theplantlist.org) [14], which is a traditional Chinese medicine with various pharmacological activities including hypoglycemic, antioxidant, neuroprotective, anti-inflammatory, hepatoprotective and kidney protective effects [15]. Cornuside was found decreased the number of Th17 cell-infiltrating lesions, the number of Th17 cells in the blood, and the serum levels of IL-6, IL-23, and IL-17A in rats experimental autoimmune encephalomyelitis model, which improved the neurological function of the spinal cord and inhibited inflammatory infiltration and demyelination [16]. Cornuside also inhibits the production of inflammatory factors, such as NO, PGE2, and TNF-α by macrophages in a dose-dependent manner [17]. It has demonstrated has good anti-inflammatory effects in various inflammatory diseases, including osteoarthritis of the knee [18], septicaemia [19], and mast cell-mediated anaphylactic reactions [20]. Additionally, it is clinically safe and exhibits limited toxicity at high concentrations [15]. However, the protective effect of cornuside on psoriasis is still not clear yet.

This study aims to investigate the roles and mechanisms of cornuside in psoriasis at the cellular and animal levels by targeting macrophages. It demonstrated that cornuside can effectively alleviate psoriasis-like symptoms, and significantly reduce the number of immune cells and the levels of inflammatory factors in the skin tissues. The inhibitory effects of cornuside on immune activation (especially the macrophages) in the pathogenesis of psoriasis will lead to an important area of research. It may provide new choices and strategies for the treatment of psoriasis.