Natural Product-Derived Compounds Targeting Keratinocytes and Molecular Pathways in Psoriasis Therapeutics

Abstract

Psoriasis is a chronic autoimmune inflammatory skin disorder that affects approximately 2-3% of the global population due to significant genetic predisposition. It is characterized by an uncontrolled growth and differentiation of keratinocytes, leading to the formation of scaly erythematous plaques. Psoriasis extends beyond dermatological manifestations to impact joints and nails and is often associated with systemic disorders. Although traditional treatments provide relief, their use is limited by potential side effects and the chronic nature of the disease. This review aims to discuss the therapeutic potential of keratinocyte-targeting natural products in psoriasis and highlight their efficacy and safety in comparison with conventional treatments. This review comprehensively examines psoriasis pathogenesis within keratinocytes and the various related signaling pathways (such as JAK-STAT and NF-κB) and cytokines. It presents molecular targets such as high-mobility group box-1 (HMGB1), dual-specificity phosphatase-1 (DUSP1), and the aryl hydrocarbon receptor (AhR) for treating psoriasis. It evaluates the ability of natural compounds such as luteolin, piperine, and glycyrrhizin to modulate psoriasis-related pathways. Finally, it offers insights into alternative and sustainable treatment options with fewer side effects.

Keywords: inflammation; keratinocyte; natural products; psoriasis; signaling pathway.

Figure 1

Signaling pathways in psoriasis pathogenesis in keratinocytes. This diagram illustrates the intricate network of cytokine signaling pathways that are activated within keratinocytes by key proinflammatory cytokines such as IL-17A, IL-22, IFN-γ, and TNF-α, which are secreted by various immune cells. The complex interplay of cytokines, signaling cascades, and transcriptional regulators promotes the hyperproliferation, aberrant differentiation, and chronic inflammation observed in psoriatic keratinocytes. IFN-γ binding to its receptor activates the Janus kinase 1/2-signal transducer and activator of transcription 1 (JAK1/2-STAT1) signaling. Phosphorylated STAT1 induces the expression of C-X-C motif chemokine ligand 9 (CXCL9), CXCL10, and CXCL11. Similarly, TNF-α binding to the TNF receptor (TNFR) activates complex I, which comprises TNF receptor-associated death domain (TRADD), TNF receptor-associated factor 2 (TRAF2), receptor-interacting protein, and cellular inhibitor of apoptosis proteins (cIAPs). In turn, these activate the TGF-beta-activated kinase 1 (TAK1), mitogen-activated protein kinases (MAPKs), activator protein 1 (AP1), I-kappa-B kinase (IKK), inhibitor of kappa B (IκB), and nuclear factor-kappa B (NF-κB) pathways. The translocation of AP1 induces S100 calcium-binding protein A8 (S100A8), human beta-defensin 2 (hBD-2), hBD-3, and S100A7 expression, whereas NF-κB activation induces C-C motif chemokine ligand 20 (CCL20), keratin 17 (KRT17), prostaglandin-endoperoxide synthase 2 (PTGS2), vascular endothelial growth factor (VEGF), interleukin 6 (IL-6), IL-8, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1) expression. Additionally, IL-17A activates the MAPK, NF-κB, and STAT3 pathways by binding to the IL-17 receptor A/IL-17 receptor C (IL-17RA/IL-17RC) heterodimer. The IL-22 receptor 1/IL-10 receptor 2 (IL-22R1/IL-10R2) heterodimer activates STAT3 by phosphorylating tyrosine kinase 2 (TYK2) and JAK1 and inducing CCL20 and KRT17 expression. Additionally, IL-22 binding protein (IL-22BP) inhibits IL-22 activity by directly binding to it. Image created using BioRender.com (https://www.biorender.com (accessed on 13 March 2024)). Sharp arrows (→) indicate activation, and blunt arrows (⊣) indicate inhibition. Upward arrows (↱) indicate transcriptional activation.

Figure 2

Putative molecular targets and their associated signaling pathways for psoriasis in keratinocytes. TNF-α activates Trim33, which induces K63 ubiquitination of annexin A2. Subsequently, K63 ubiquitination of annexin A2 activates the NF-κB signaling pathway. TNF-α also activates the FABP5-VCP complex, which in turn activates NF-κB. SIRT1 inhibits NF-κB signaling, while HMGB1 activates it. IL-17A or TNF-α activates p38, promoting psoriasis development. AhR increases IL-37 expression, and increased IL-37 inhibits p38 activity. TNF-α or IL-17A activates ERK, while DUSP1 inhibits the ERK pathway. IL-17A or IFN-γ activates the NLRP3 inflammasome, which converts pro-IL-1β to IL-1β. Activated IL-1β is involved in psoriasis pathogenesis. IFN-γ activates AIM-2, which also converts pro-IL-1β to IL-1β. IL-22 activates STAT3, and SIRT1 inhibits STAT3 activity. Sharp arrows (→) indicate activation, and blunt arrows (⊣) indicate inhibition. Yellow circles represent K63 ubiquitination of annexin A2.

Figure 3

Chemical structures of natural product-derived compounds used in psoriasis treatment. The figure shows the chemical structures of 14 different compounds (luteolin, piperine, glycyrrhizin, kaempferol, punicalagin, shikonin, genistein, nitidine chloride, leucosceptoside A, indirubin, paeoniflorin, 3H-1,2-dithiole-3-thione (D3T), liquirtin, and cudraxanthone D). The chemical structures were generated using ChemDraw (Ver. 23.1.1).

Figure 4

Potential molecular targets of natural product-derived compounds for psoriasis treatment. TNF-α, IL-17A, IL-22, IL-1α, Oncostatin-M, and IFN-γ promote the activation of STAT3, STAT1, TAK1/NF-kB, JNK, AKT, and p38 signaling systems, as well as ROS production. These signaling pathways and ROS production lead to inflammatory responses by increasing the expression or protein levels of NLRP3, caspase-3, caspase-1, and others in keratinocytes. They also contribute to abnormal keratinocyte proliferation by increasing the levels of SKP2, CEBPD, cyclin A, and cyclin D1. Piperine, shikonin, and genistein inhibit STAT3, while glycyrrhizin inhibits STAT3 activity through SIRT1 activation. Kaempferol and cudraxanthone D (Cud D) also inhibit STAT1 activity. Luteolin, genistein, Cud D, and liquirtin inhibit NF-kB transactivity, whereas indirubin inhibits NF-kB signaling by inhibiting TAK1 activity. 3H-1,2-dithiole-3-thione (D3T) and nitidine inhibit the JNK signaling pathway, a member of the MAPK signaling system, and indirubin and paeoniflorin inhibit p38, another signaling pathway. Leucosceptoside A (Leu A) inhibits the PI3K/AKT signaling pathway, while Leu A and kaempferol inhibit ROS overproduction. Furthermore, p53 is known to inhibit excessive keratinocyte proliferation, and nitidine activates the p53 pathway. Sharp arrow (→) indicates activation, and blunt arrow (⊣) indicates inhibition.