In a recent review published in Signal Transduction and Targeted Therapy, researchers reviewed existing data on psoriasis etiopathogenesis and treatment.
Study: Signaling pathways and targeted therapies for psoriasis. Image Credit: Flystock/Shutterstock.com
Background
Psoriasis is a prevalent, chronic, inflammatory skin condition that affects people, healthcare institutions, and society. Despite advancements in therapy, the processes behind less predominant types remain a mystery.
Severe side effects and illness recurrence after therapy discontinuation are concerning. Understanding psoriasis pathophysiology is critical for new research findings, therapeutic approaches, and extended clinical treatment choices.
About the review
In the present review, researchers elucidated the biological mechanisms underlying psoriasis development and described current treatment options and those undergoing clinical trials.
Biological pathways and signaling mechanisms underlying Psoriasis
Psoriasis is a chronic skin condition characterized by increased immune cells such as T helper 1 (Th1), Th17, and Th22 cells.
These cells secrete interleukin-22 (IL-22), which binds to IL-22 receptors on target cells, activating downstream signals in keratinocytes, inducing the production of antimicrobial proteins, and inhibiting keratinocyte differentiation, resulting in acanthosis, a typical psoriasis-like inflammation of the epidermis.
Tumor necrosis factor-alpha (TNF-α) may boost the impact of IL-22. Tumor necrosis factor-interleukin 23-interleukin 17 pathways are associated with psoriasis pathophysiology, particularly plaque psoriasis.
Dendritic cells (DCs) are the primary secretors of interleukin 12 and interleukin 23, with ribonucleic acid (RNA0 expression of p19 and p40 rising significantly in psoriasis lesions.
IL-23 operates on T lymphocytes, especially helper T [cluster of differentiation 4+ (CD4+] cells, through a cell-based receptor complex composed of transmembrane proteins IL-12R1 and IL-23R. IL-23 stimulates the interleukin-17 production, a critical cytokine implicated in psoriasis pathophysiology.
IL-17A, C, and F are associated with psoriasis due to their elevated levels in psoriasis lesions. TNF-α primarily works on target cells via two kinds of TNF receptors, TNFRI (p55) and TNF-RII (p75). It dramatically reduces plasmacytoid dendritic cell (pDC) IFN-secretion, promoting pDC maturation to a more conventional dendritic cell phenotype capable of producing IL-23. TNF-α also works with IL-17A to coregulate psoriasis-related cytokines and keratinocyte genes, influencing keratinocyte function.
C-C Motif Chemokine Ligand 20 (CCL20), also known as macrophage inflammatory protein 3 (MIP-3), is a crucial chemokine in psoriasis; however, it only binds to the C-C chemokine receptor 6 (CCR6).
Scratching or trypsinization can boost CCL20 synthesis by keratinocytes in psoriatic lesions and release CCR6+ Th17 cells, which generate IL-17A and further promote CCL20 selection. Metabolic alterations have been implicated in psoriasis pathogenesis, especially those involved in regulating keratinocytes and associated immune cells.
Treatment targeting metabolic variables may be a viable option for managing psoriasis. Psoriasis is distinguished by increased CD147 on neutrophils, which causes chemotaxis. The nuclear factor kappa B (NF-κB) pathway regulates keratinocyte and immune cell proliferation and differentiation.
Wnt signaling is also altered, with Wnt-5a increased and WIF-1 downregulated in psoriatic lesions. L-type amino acid transporter 1 (LAT1)-mediated amino acid absorption inhibition may aid in managing skin inflammation. Lysophosphatidic acid (LPA), phosphatidylinositol (PI), and LysoPC, which are involved in glycerophospholipid metabolism, are elevated in the plasma of psoriasis patients.
Targeted therapies for psoriasis
Psoriasis treatment aims to reduce inflammation, remove skin lesions, enhance quality of life, and avoid complications by eliminating lesions, lowering itching, and improving the patient's quality of life.
Treatment options for mild psoriasis include topical corticosteroids, calcipotriol, and their combination. In moderate-severe psoriasis cases unresponsive to topical treatments, oral drugs such as retinoids, cyclosporine, and methotrexate are used.
Methotrexate has been licensed by the Food and Drug Administration (FDA) for over 50 years. Still, cyclosporine is used for severe psoriasis, although it is associated with various adverse effects such as renal toxicity.
Acitretin is used to manage pustular and erythrodermic psoriasis; however, it is contraindicated for pregnant individuals due to its teratogenicity. Phototherapy, which includes psoralen and ultraviolet-A (PUVA), narrow-band UVB (NB-UVB), and wide-band UVB, is an essential therapeutic option for moderate to severe psoriatic lesions.
TNF-α inhibitors, IL-17 inhibitors, IL-12/IL-23p40 inhibitors, IL-23 inhibitors, IL-36/IL-1 inhibitors, Janus kinase (JAK) inhibitors, Phosphodiesterase 4 (PDE4) inhibitors, IL-22 inhibitors, and IFN inhibitors are examples of biologics used to treat psoriasis.
RORγT-targeted drugs (JTE-451, mesenchymal stem cells), aryl hydrocarbon receptor (AhR)-targeted agents (topical tapinarof), and sphingosine 1-phosphate receptor 1 (S1PR1)-targeted agents (Ponesimod) are among the therapies under clinical trials. Some medications can modify deoxyribonucleic acid (DNA) methylation, impacting inflammation and immunological responses, making it a potential therapeutic target for psoriasis.
Conclusion
Overall, the review findings highlighted altered signaling pathways in psoriasis pathogenesis, which could be targeted to develop novel and effective interventions to reduce the health burden of the disease.
While progress has been made in understanding and treating psoriasis, further research is needed to determine if genetic indicators and biomarkers can predict early diagnosis and intervention. Additionally, there is a lack of comprehensive understanding of metabolic effects in psoriasis.
Novel genetic link uncovered in generalized pustular psoriasis