Targeting psoriatic inflammation with natural compounds: mechanistic insights and therapeutic promise

It was previously believed that Th1 cells were the primary immune response mediators in psoriatic plaques. Studies have shown that IL-4 can enhance the results of illness by increasing the levels of epidermal GATA3 mRNA and protein, and at the same time decreasing the levels of IL-1β and IL-6 through transcriptional and post-transcriptional mechanisms (Aydogan et al. 2013). Improving the expression of IL-6, IL-8, TNF-α, and hBD2, differentiating Th17 and Th22 cells, and triggering the release of IL-17 and IL-22 are all IL-1β's functions. Blocking this pathway allows the Th2 cytokine IL-4 to regenerate healthy skin in psoriatic skin (Onderdijk et al. 2015). Psoriasis patients' mesenchymal stem cells (MSCs) have been shown to have an upregulation of genes that encode Th1 cytokines, but not Th2 cytokines, when compared to healthy controls (Campanati et al. 2014). The bidirectional response pattern of Th1/Th2 equilibrium clearly reveals the differences between the paradigms. Th2 cytokines (IL-4, IL-10) in erythrodermic psoriasis (EP) show higher levels than in psoriasis vulgaris (PV) (Zhang et al. 2014). Those who suffer from psoriasis and skin that is affected have increased levels of Th1 cells and IFN-γ. At the onset of the psoriatic cascade, interferon-γ has a role in promoting the production of CCL20, IL-17 + T cells, and γ-defensin2 (HBD-2), which is a protein that is both antimicrobial and chemotactic in nature. Psoriatic keratinocytes are responsible for the overexpression of this protein (Kryczek et al. 2008). It has been found that dysregulated keratinocytes, which include IL-1β and IL-18, are responsible for the release of AMP and IL-1 family cytokines, which then leads to the development of Th1 and Th17 cells (Anderson et al. 2015).

The cytokines IL-1β, TGF-β, IL-6, and IL-23, as well as the transcription factor RORγt, regulate the development of Th17 cells. Psoriatic skin lesions contain high numbers of CD4 + T cells that produce IL-17, indicating that Th17 cells play a crucial role in the immunopathogenesis of psoriasis (Fujishima et al. 2010). To heighten the inflammatory response of keratinocytes, Th17 cells secrete IL-17, IL-12, IL-22, and IL-9. To improve the immune response in psoriasis, keratinocytes secrete chemokines, cytokines, and antimicrobial peptides such as CCL20 and CXCL1, 3 (Ottaviani et al. 2006). An IL-23/Th17 axis positive feedback loop is established when activated Th17 cells enhance the inflammatory response. According to recent animal research, the Th17 pathway plays a pivotal role in the pathogenesis of psoriasis. There is some evidence that anti-IL-23 antibody inhibition of the IL-23/Th-17 pathway may slow the course of psoriatic disease. Antibodies or knockout mice that lack IL-22 are able to inhibit IL-23-induced skin thickening (Büchau and Gallo 2007). Dysregulated IL-17 signaling and Th17 cell pathway activity facilitate persistent inflammation in psoriasis. The primary objective of ongoing therapeutic trials is to reverse this dysfunction (Deng et al. 2016).

Several stimuli, including as TGF-γ, IL-4, IFN-γ, IL-2, and IL-6, impact the polarization of regulatory T (Treg) cells. Foxp3, TGF-β, IL-10, perforin, and granzyme A are expressed by mature Treg cells. They facilitate the preservation of peripheral tolerance, mitigate chronic inflammatory disorders, and avert autoimmune diseases (Campbell and Koch 2011; Bell et al. 2015). Treg cells may inhibit other immune cells, such as Th17 cells. IL-6, essential for Treg cell development, inhibits Th17 cell activation and proliferation, hence establishing a balance between Tregs and Th17 cells. Elevated Treg cell numbers have been noted in the skin lesions of individuals with psoriasis (Dhaeze et al. 2015). In models of psoriasis, the deletion of CD18 from Tregs results in the hyperproliferation of T cells that are responsible for pathogenic immunity. In the Cd18hypo PL/J mouse model, it was found that decreased CD18 expression led to poor functioning of Treg cells as well as decreased proliferation of these cells. Using adoptive transfer, Cd18wt Tregs were transferred into Cd18hypo PL/J mice, which resolved Treg cell malfunction and improved the outcomes of the psoriasis study (Wang et al. 2008). Recently, IMQ-treated mice exhibited improved psoriasis-like skin lesions, reduced Th17 cytokine levels, and elevated Treg cell counts. CD4 + CD25 + T cells generated in vitro from the hematopoietic cells of psoriasis patients exhibit diminished regulatory functions (Kim et al. 2015).

There is a strong connection between immune cells and psoriasis, specifically CD4 + T cells which create IL-9 and γά T cells which produce IL-17. The inflammatory cytokines IL-17, IL-22, and IL-9 are generated by these cells and play a role in the development of psoriasis (Cai et al. 2013). γδT cells enhance a Th17 inflammatory response by secreting IL-17 after being quickly activated by IL-23, IL-1β, or danger signals. Studies show that T-cell receptor δ-deficient (Tcrd − / −) mice have significantly decreased levels of inflammation, epidermal hyperplasia, and IL-17 (Cai et al. 2011). Furthermore, cutaneous inflammation and acanthosis caused by IL-23 or IMQ are exclusively observed in wild-type (WT) mice (Van Der Fits et al. 2009). Human investigations have identified a substantial presence of IL-17-secreting γδT cells in lesions of psoriasis patients, with dermal γδT cells serving as a major source of IL-17 and CCR6 following IL-23 activation in the skin. Vγ9Vδ2 T lymphocytes, elevated in the skin yet diminished in the peripheral blood of psoriasis patients, migrate from the bloodstream to the skin to contribute to psoriasis pathogenesis (Laggner et al. 2011). IL-22-secreting Th22 cells and IL-9-secreting Th9 cells constitute additional unique subsets of effector T cells. Research on γδT, Th22, and Th9 cells in psoriasis is anticipated to increase, enhancing comprehension of the mechanisms underlying inflammatory responses and the pathophysiology of psoriatic illness (Lowes et al. 2014).

You might be surprised to know that the PSORS1 gene is a component of the MHC. CD8 + T cells in psoriasis patients' blood often carry the HLA-Cw6 gene, the disease's most important susceptibility locus (Volarić et al. 2019). Cell surface antigens recognized by CD8 + T lymphocytes in psoriatic skin lesions included keratin and epitopes shared by Streptococcal M proteins (Johnston et al. 2004). The fact that perforin-mediated cytotoxicity of CD8 + T cells destroys psoriasis keratinocytes provides more evidence that CD8 + T cells have a role in the development of the disease. Psoriasis progresses in part because CD8 + T lymphocytes generate apoptotic keratinocytes, which initiate a destructive cycle of regenerative hyperplasia in epidermal keratinocytes (Deng et al. 2016).

The innate immune system activates NKT cells promptly during the immune response because of their capacity to deliver direct cytotoxic effects and swiftly generate cytokines. This encompasses interferon-gamma (IFN-γ), which facilitates a Th1-mediated inflammatory response, and interleukin-4 (IL-4), which endorses Th2 cell development. The dysregulation or hyperactivation of NKT cells has been linked to the pathophysiology of various immune-related disorders, including multiple sclerosis, inflammatory bowel disease, and allergic contact dermatitis (Hugh and Weinberg 2018). NKT cells in psoriasis are situated within the epidermis, in close proximity to keratinocytes, indicating their role in direct antigen presentation. Furthermore, CD1d, a protein essential for NKT cell activation, is extensively increased in the epidermis of psoriatic lesions, unlike its restricted expression in terminally differentiated keratinocytes under normal circumstances. An in vitro investigation simulating psoriasis-like cytokine-driven inflammation subjected cultured CD1d-expressing keratinocytes to interferon-gamma alongside α-galactosylceramide, a glycolipid antigen from the lectin family, to evaluate immune activation (Dunphy and Gardiner 2011). Interferon-gamma (IFN-γ) was found to augment CD1d expression on keratinocytes, leading to their activation and the subsequent stimulation of NKT cells. This interaction resulted in a significant elevation of IFN-γ production by NKT cells, although IL-4 remained unmeasurable. The predominant production of IFN-γ indicates a bias toward a Th1-mediated immune response facilitated by NKT cells, which contributes to the immunopathogenesis of psoriasis (Dunphy and Gardiner 2011).

Psoriatic skin has a significant accumulation of several antigen-presenting cell types, especially myeloid and plasmacytoid dendritic cells, in the epidermis and dermis relative to non-lesional skin. Dermal dendritic cells are involved in eliciting inflammatory responses through the production of IL-12 and IL-23, which facilitate the activation and development of Th1 and Th17 cells, respectively (Liu and Cao 2015). The diverse biological response secretes cytokines, triggering a cascade involving keratinocytes, fibroblasts, endothelial cells, and neutrophils that generate the skin lesions typical of psoriasis (Di Cesare et al. 2009).

Both the antigen-presenting capacity of dendritic cells and the infiltration of T lymphocytes are influenced by TNF-α. In psoriasis, the levels of NF-κB are elevated, and this cytokine partially accomplishes its purpose by phosphorylating it (Goldminz et al. 2013). TNF-α acts as a regulator of the IL-23/Th17 axis and promotes IL-23 production by dendritic cells in psoriasis, suggesting that it possesses pro-inflammatory properties. By blocking IL-23 and reducing levels of Th17 effector molecules like IL-17, IL-22, chemokines, and β-defensin, Etanercept and other TNF-α inhibitors accomplish their immunological purpose. Th17 cells are directly affected by TNF-α in psoriasis, because it decreases autonomous TNF/TNFR2 signaling (Shiga et al. 2015).

In the early stages of the disease, IFN-γ is more important, according to research. STAT3 is activated as a result of Janus kinase 1 (JAK2) and JAK3 being cross-phosphorylated by Interferon-gamma (IFN-γ). The activation of STAT factors plays a critical role in cell proliferation and has the ability to regulate several genes that are expressed in psoriatic skin lesions (Johnson-Huang et al. 2012). The release of cytokines (IL-23, IL-1), chemokines (CXCL10, CXCL11), and adhesion molecules from dendritic cells is induced by IFN-γ. Investigations suggest that IFN-γ, because of its favorable correlation with PASI, could function as a biomarker for the activity of psoriasis illness (Madonna et al. 2010).

Blood and skin samples taken from patients with psoriatic arthritis show increased levels of IL-17 mRNA and protein. Th17 cells are mostly responsible for IL-17 production, but new research shows that innate immune cells, such as γδT cells, neutrophils, and mast cells, also play a role in IL-17 release in psoriasis (Isailovic et al. 2015). There are at least six homodimeric cytokines that make up the IL-17 family, and they are IL-17A through IL-17F. The two ILs that are most relevant to psoriatic disease are IL-17A and IL-17F. The antimicrobial protein REG3A, which is involved in wound healing, acts as a downstream mediator between IL-17 and keratinocytes, enhancing their proliferation and inhibiting their differentiation (Lai et al. 2012). It has been demonstrated in the past that IL-17A causes keratinocytes to produce chemokines and antimicrobial peptides. The inflammatory response in psoriasis is sustained by keratinocytes, which in turn attract Th17 cells and enhance IL-17 production, forming a positive feedback loop (Ramirez-Carrozzi et al. 2011).

Th17 cells cannot survive or proliferate without IL-23. IL-23 accelerates the development of psoriasis by stimulating the overproduction of keratinocytes. Members of the IL-12 family include IL-23 as well as IL-12. The IL-12 P40 subunit is shared by both IL-12 and IL-23, although p35 and p19 are different subunits found in each of these two proteins (Lee et al. 2004). The main producers of interleukin-12 and interleukin-23, which are found in higher amounts in psoriatic skin, are dendritic cells and macrophages. While p35 levels do not change, new studies show that p19 and p40 mRNA are higher in lesional skin than in non-lesional skin. To summarize, IL-23, not IL-12, is the main factor that causes psoriasis. The amounts of IL-23 protein in psoriatic skin lesions are much higher than in non-lesional skin (Yawalkar et al. 2009).

Th17 and Th22 cells mediate the effect of IL-22 on IL-23-induced keratinocyte hyperproliferation in both in vivo and in vitro settings through STAT3 signaling. Because it is exclusively expressed by epithelial cells (e.g., skin keratinocytes) and bound to its heterodimeric receptor (IL-22RA and IL-10 receptor B), IL-22 exerts its effects in tissues. People with psoriasis often have elevated IL-22 levels in their blood (Mashiko et al. 2015). The interaction between interleukin-22 and interleukin-17 inhibits keratinocyte differentiation while increasing their proliferation and motility, leading to nuclear retention within the stratum corneum, epidermal hyperplasia (acanthosis), and elongation of the epidermal rete ridges (papillomatosis) all of which are characterized by psoriatic skin plaques (Becher and Pantelyushin 2012).

In comparison to healthy skin from control subjects, psoriatic lesional skin expressed significantly more IL-9. Research carried out by Singh et al. indicates that the skin of psoriatic mice models shows an increase in IL-9R and IL-9 expression following intradermal injection of IL-9, which initiates a Th17-related inflammatory response (Singh et al. 2013). The pro-inflammatory cytokine IL-9 secretes IFN-γ, TNF-α, IL-17, and IL-13 in psoriasis. There is IL-9 secretion by both Th9 and Th17 cells. In addition to blocking IL-9 signaling, the anti-IL-9 monoclonal antibody decreases IL-17 synthesis, which in turn diminishes Th17 functioning in another model of autoimmune illness. This data points to IL-9 as a potential mediator or target of the IL-23/Th17 pathway suppressor (Witte et al. 2014). While, near the IL-9 gene locus on chromosome 5q31.1-q33.1 is a psoriasis susceptibility gene (Deng et al. 2016).

One of the basic mechanisms is superantigens. A large number of superantigens are usually produced by bacterial isolates. To connect antigen-presenting cells to T-helper cell receptors, superantigens cling to the outside surface of MHC class II proteins. After then, T cells become active, which causes them to multiply and produce cytokines like IFN-γ (Yan et al. 2017). Overstimulation, on the other hand, causes energy-related T-cell failure and dysfunction. In addition, superantigens increase the synthesis of the skin-homing receptor, cutaneous lymphocyte antigen, by T cells, which helps with Th17-dominated responses (Hedin et al. 2021). Peptidoglycan (PG) is involved in a distinct process. Dendritic cells and macrophages can take up peptidoglycan from bacteria in the intestines or tonsils, and then, dendritic cells and macrophages can go to the skin to provide peptidoglycan peptides to clones of Th1 cells that are specific to antigens. Keratinocytes are influenced by cytokines, especially IFN-γ. In the end, the epidermal layer becomes too proliferant and fails to differentiate adequately (Zhou and Yao 2022).

Researches indicate the significant role of viral infections in the pathophysiology of psoriasis, proposing that deregulation of host antiviral immune responses initiates the inflammatory skin conditions associated with the disease's development (Zhu et al. 2017). Viruses (namely, HIV, HCV, and HPV) play a role in psoriasis. Cell proliferation occurs through PKC-dependent or -independent pathways, facilitated by the tat gene, which in turn causes HIV replication. IFN-γ, cathelicidin, and TLR9 are all genes that HCV boosts in order to make inflammation easier. When anti-HPV antibodies bind to viral proteins, it triggers the activation of complement and the development of Munro's microabscesses (Teng et al. 2021).

Some clinical studies suggest a possible connection between fungus and psoriasis. Some species of Malassezia yeasts, such as those associated with guttate and scalp psoriasis, have been associated to different forms of the skin condition (Aydogan et al. 2013). In addition, Candida albicans infection has been linked to newborn diaper psoriasis (Bonifaz et al. 2016). Based on these findings, it was postulated that psoriasis develops when fungus, including the scalp-found Malassezia ovalis, trigger the alternative complement pathway. After 4 weeks of treating four cases of scalp psoriasis with ketoconazole, the lesions improved and the researchers found no evidence of fungal growth on the scales (Zhou and Yao 2022). Several epidemiological studies have shown that Candida albicans and Malassezia spp. are the most common types of fungi associated with psoriasis. According to the characteristics of these fungi, the majority of fungal infection sites in psoriasis patients are found in skin creases and places where sebum accumulates (Vijaya Chandra et al. 2021). By affecting the development of specific types of T cells, malassezia can bring on or worsen psoriasis in those who already have it. Malassezia glabrata's hydrophobic components cause human epidermal keratinocytes to produce inflammatory proteins, which in turn cause peripheral blood Th1-biased differentiation of Th cell subsets. The study found that the fungus Malassezia furfur affects cell migration and proliferation by increasing the expression of transforming growth factor-β1, integrin chains, and HSP70 in human keratinocytes. The subjects included both positive and negative skin biopsies from psoriasis patients (Baroni et al. 2004). The Candida albicans surface proteins behave as superantigens, which trigger the activation of certain Vβ family T lymphocytes even in the absence of antigen presentation, leading to an excess of pro-inflammatory cytokines (Javad et al. 2015). Interleukin-23 (IL-23) facilitates the multiplication and survival of Th17 cells, which are essential for combating Candida albicans infections. Th17 cells produce IL-17, a cytokine that attracts neutrophils to areas of infection and promotes the synthesis of antimicrobial peptides, therefore aiding in the elimination of Candida species. Nonetheless, despite the protective function of IL-17, individuals receiving monoclonal antibody therapy aimed at IL-17A or its receptor for psoriasis have exhibited a heightened occurrence of Candida infections. This indicates that although IL-17 inhibitors effectively control psoriasis, they may compromise the body's defenses against fungal infections (Furue et al. 2020).

Many studies have looked at the anti-inflammatory properties of curcumin, a polyphenolic chemical extracted from the root of the turmeric plant (Curcuma longa). Through its regulation of important signaling pathways such as NF-κB and MAPK, curcumin has been demonstrated to inhibit the production of pro-inflammatory cytokines, such as TNF-α and IL-17. This regulation is useful in psoriasis for lowering inflammation and keratinocyte growth (Zhang et al. 2022). Furthermore, oral curcumin has shown to be quite successful in lowering serum IL-22 levels in psoriasis patients (Antiga et al. 2015).

Glycyrrhizin, a triterpenoid saponin extracted from the root of Glycyrrhiza glabra (licorice), has been reported to ameliorate psoriasis-like skin lesions by inhibiting TNF-α-induced inflammatory responses through the NF-κB and MAPK signaling pathways, leading to decreased production of inflammatory cytokines (Xiong et al. 2015).

Rosmarinic acid, a phenolic compound found in rosemary (Rosmarinus officinalis), has been reported to ameliorate psoriatic skin inflammation by inhibiting the production of IL-23 and IL-17A, as well as ameliorating redness and scaling (Ho et al. 2022).

A flavonoid glycoside called Rhododendrin, which is present in the Rhododendron genus of plants, has been demonstrated to reduce skin inflammation in mice that is similar to psoriasis and is mediated via toll-like receptor-7. Reducing cytokine production is the result of its ability to downregulate the NF-κB and MAPK signaling pathways (Jeon et al. 2017).

Acids derived from the resin of Boswellia serrata have demonstrated significant anti-inflammatory effects. These substances have demonstrated the ability to suppress dendritic cell activation and reduce the secretion of pro-inflammatory cytokines, including IL-12 and IL-23, which are crucial in the pathogenesis of psoriasis (Halim et al. 2020).

Resveratrol, a polyphenolic compound found in grapes, berries, and peanuts, has been shown to exert anti-inflammatory effects by inhibiting the production of IL-17 and other inflammatory cytokines, modulating the NF-κB signaling pathway, and reducing keratinocyte proliferation in psoriasis models (Kjær et al. 2015).

There are several polyphenols in green tea (Camellia sinensis), but some of the most powerful antioxidants are catechins like epigallocatechin gallate (EGCG). Research conducted recently has shown that EGCG effectively neutralizes free radicals (Zhang et al. 2024). Also, it reduces levels of malondialdehyde (MDA) and increases activity of superoxide dismutase (SOD) and catalase (CAT), which in turn reduces inflammation similar to psoriasis caused by imiquimod in mouse models (Zhang et al. 2016).

Quercetin, a flavonoid found in many vegetables and fruits like apples and onions, has been shown to exert a powerful anti-oxidant effect in imiquimod-induced psoriasis, by increasing the activity of SOD, CAT, and GSH, as well as, decreasing MDA accumulation (Chen et al. 2017).

Carotenoids, derived from cyanobacteria have demonstrated significant antioxidative properties, primarily through their ability to scavenge ROS. These compounds not only exhibit anti-oxidant effects but also possess anti-inflammatory properties, making them promising candidates for topical treatments in psoriasis (Lopes et al. 2020).

Salidroside, a glucoside derived from Rhodiola rosea, has been demonstrated to inhibit oxidative stress signaling pathways through the activation of sirtuin 1 (SIRT1), a protein that plays a critical role in regulating cellular responses to stress. By modulating key signaling pathways, including NF-κB and MAPK, salidroside effectively reduces both inflammation and oxidative damage associated with psoriatic lesions (Xu et al. 2019).

The active compound indirubin from Indigo naturalis has shown significant anti-proliferative effects in psoriasis models. Its mechanism of action involves the inhibition of cyclin-dependent kinases (CDKs), which results in cell cycle arrest in keratinocytes. In addition to its anti-proliferative effects, indirubin also possesses anti-inflammatory properties, thereby enhancing its therapeutic potential in the management of psoriasis (Gamret et al. 2018; He et al. 2022).

Delphinidin is an anthocyanidin found in various pigmented fruits and vegetables. Delphinidin has been demonstrated to inhibit the PI3K/Akt/mTOR signaling pathway in imiquimod-induced psoriasis, which is frequently upregulated in psoriatic lesions and contributes to the excessive proliferation of keratinocytes (Chamcheu et al. 2017).

The extract of Mahonia aquifolium (Oregon grape) has been shown to inhibit keratinocyte proliferation and reduce the production of pro-inflammatory cytokines such as IL-8. The anti-proliferative action of Mahonia aquifolium is attributed to its ability to modulate the NF-κB signaling pathway, thereby reducing inflammation and keratinocyte hyperproliferation (Zahir et al. 2013; Sarkar et al. 2023).

The ethanol extract of Artemisia capillaris has been reported to induce apoptosis in hyperproliferative keratinocytes, alleviating psoriatic symptoms (Lee et al. 2018). This mechanism is crucial in counteracting the excessive proliferation characteristic of psoriasis.

Qingre Huoxue decoction is a traditional herbal formulation recognized for its significant anti-angiogenic effects in psoriasis-like skin conditions. This formulation has been shown to reduce levels of key angiogenic factors, including VEGF, HIF-1α, and Flt-1. By modulating these factors, Huoxue decoction effectively contributes to decreased vascular permeability and inflammation (Li et al. 2021).

PSORI-CM02 formulation consists of five herbal components: Rhizoma Curcumae, Radix Paeoniae rubra, Sarcandra glabra, Rhizoma Smilacis glabrae, and Fructus mume. It has been shown to possess anti-angiogenic efficacy both in vitro and in vivo by downregulating VEGF and HIF-1α, while also inhibiting the proliferation and tube formation of HUVECs. Through these mechanisms, PSORI-CM02 effectively disrupts the oxidative stress–inflammation–angiogenesis axis, contributing to its therapeutic potential in managing psoriasis (Lu et al. 2021).

Rottlerin, a polyphenol natural product isolated from the Asian tree Mallotus philippensis, has been demonstrated to reduce the ability of HUVECs to form capillary-like structures, indicating its potential as an anti-angiogenic agent in psoriasis (Min et al. 2017).

Vitamin D and its analogs are commonly employed in the management of chronic plaque psoriasis, particularly in mild-to-moderate cases. Their introduction into clinical use was based on early observations that both oral and topical forms exhibit beneficial effects on psoriatic plaques (Bhat et al. 2022). Mechanistically, vitamin D analogs, such as calcipotriol, calcitriol, and tacalcitol, act by binding to intracellular vitamin D receptors (VDR) in keratinocytes. Once activated, these receptor–ligand complexes regulate gene transcription through vitamin D response elements (VDREs), affecting pathways involved in keratinocyte proliferation, differentiation, and inflammation (Pike et al. 2012; Bikle 2014).

The genetic regulation of the VDR is implicated in psoriasis. Polymorphisms in the VDR gene are linked to altered VDR mRNA expression, which may compromise the cutaneous barrier and exacerbate psoriasis (Richetta et al. 2014). Vitamin D also modulates immune responses by downregulating inflammatory cytokines (e.g., IL-6, IL-8, TNF-α, IFN-γ) while promoting anti-inflammatory mediators such as IL-10 (Karthaus et al. 2014; Prtina et al. 2021). This immunomodulatory activity is complemented by the suppression of cyclin D and c-Myc, enhancement of intracellular calcium signaling, and inhibition of keratinocyte hyperproliferation (Svendsen et al. 1997; Bikle 2011).

To address the limitations of conventional vitamin D formulations, advanced drug delivery systems, such as nanostructured lipid carriers (NLCs) and solid lipid nanoparticles (SLNs), have been developed. These systems aim to improve skin penetration, reduce local irritation, and provide sustained drug release, thereby enhancing therapeutic outcomes and patient compliance (Lin et al. 2010).

For instance, calcipotriol-loaded NLCs, especially when co-loaded with methotrexate (CAL-MTX-NLCs), demonstrated a significant improvement in skin targeting, with enhanced delivery of methotrexate (2.4–4.4 times) and reduced calcipotriol release, mitigating the risk of irritation (Lin et al. 2010).

Similarly, dual-loaded SLNs incorporating cyclosporin and calcipotriol achieved ultra-nano sizes (< 100 nm) and high encapsulation efficiency. In vivo studies on psoriatic mouse models revealed that these NLC-based formulations outperformed both SLNs and traditional preparations in reducing skin inflammation and lesion severity (Arora et al. 2017).

Despite these promising results, nanocarrier-based formulations are still largely in the preclinical or early clinical stages. Their long-term safety, manufacturing scalability, and cost-effectiveness remain significant barriers to widespread clinical adoption. Additionally, the complexity of these systems may increase the risk of formulation instability and regulatory challenges.

Topical corticosteroids (TCS) have long been a mainstay in the treatment of mild-to-moderate psoriasis, owing to their potent anti-inflammatory, immunosuppressive, anti-proliferative, and vasoconstrictive effects. These therapeutic actions are mediated through both genomic and non-genomic pathways. Upon binding to cytoplasmic glucocorticoid receptors (GR), corticosteroids induce translocation of GR complexes into the nucleus, where they interact with glucocorticoid response elements (GREs) to upregulate anti-inflammatory genes (e.g., IL-10, DUSP-1) and suppress pro-inflammatory mediators like IL-1, IL-6, TNF-α, and chemokines, such as MCP-1 and IL-8 (McManus 2003; Zhang et al. 2009; Lee et al. 2021; Lee and Tran 2023). Simultaneously, CS suppresses the transcription of pro-inflammatory genes by inhibiting transcription factors like nuclear factor-κB (NF-κB) and activator protein 1 (AP-1), which are responsible for the expression of cytokines, chemokines, and other inflammatory mediators (Patil et al. 2018; Cacheiro-Llaguno et al. 2022; Sardana and Sachdeva 2022). Moreover, CS induces MAPK phosphatase 1 (MKP-1), which deactivates MAPKs (e.g., c-Jun), leading to reduced pro-inflammatory signaling. Defects in MKP-1 expression are associated with glucocorticoid resistance (Uva et al. 2012; Sardana and Sachdeva 2022; Milara et al. 2023).

Additionally, corticosteroids promote the expression of annexin A1, a mediator that inhibits phospholipase A2 (PLA2), thus limiting the synthesis of prostaglandins and leukotrienes (Perretti and Dalli 2009; Kwatra and Mukhopadhyay 2018). These effects help resolve inflammation, reduce keratinocyte hyperproliferation, and induce apoptosis in immune cells such as eosinophils and lymphocytes. TCS also exert vasoconstrictive effects that reduce blood flow to psoriatic lesions, limiting the influx of inflammatory cells (Kwatra and Mukhopadhyay 2018).

Despite their effectiveness, the long-term use of TCS is limited by a number of well-documented drawbacks. These include cutaneous atrophy, telangiectasia, tachyphylaxis, and in some cases, systemic effects such as adrenal suppression (Niculet et al. 2020; Chandy et al. 2023).

Clinical trials have demonstrated that while short-term use is generally safe, prolonged or inappropriate application especially of high-potency corticosteroids can result in irreversible skin damage and loss of treatment responsiveness (Lebwohl et al. 2001; Castela et al. 2012b),

To mitigate these adverse effects, combination therapies are frequently employed. For instance, pairing corticosteroids with vitamin D analogs (e.g., calcipotriol) enhances efficacy while reducing the required steroid dose and minimizing atrophy (Menter and Griffiths 2007). Additionally, agents like tazarotene (a topical retinoid), salicylic acid, and calcineurin inhibitors have been combined with corticosteroids to further modulate inflammation and keratinocyte behavior (Draelos 2022).