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Review
. 2023 Nov 27;8(1):437.
doi: 10.1038/s41392-023-01655-6.

Signaling pathways and targeted therapies for psoriasis

Jia Guo #  1   2   3   4 , Hanyi Zhang #  1   2   3   4 , Wenrui Lin #  1   2   3   4 , Lixia Lu  1   2   3   4 , Juan Su  5   6   7   8 , Xiang Chen  9   10   11   12
Affiliations
Review

Signaling pathways and targeted therapies for psoriasis

Jia Guo et al. Signal Transduct Target Ther. .

Erratum in

Abstract

Psoriasis is a common, chronic, and inflammatory skin disease with a high burden on individuals, health systems, and society worldwide. With the immunological pathologies and pathogenesis of psoriasis becoming gradually revealed, the therapeutic approaches for this disease have gained revolutionary progress. Nevertheless, the mechanisms of less common forms of psoriasis remain elusive. Furthermore, severe adverse effects and the recurrence of disease upon treatment cessation should be noted and addressed during the treatment, which, however, has been rarely explored with the integration of preliminary findings. Therefore, it is crucial to have a comprehensive understanding of the mechanisms behind psoriasis pathogenesis, which might offer new insights for research and lead to more substantive progress in therapeutic approaches and expand clinical options for psoriasis treatment. In this review, we looked to briefly introduce the epidemiology, clinical subtypes, pathophysiology, and comorbidities of psoriasis and systematically discuss the signaling pathways involving extracellular cytokines and intracellular transmission, as well as the cross-talk between them. In the discussion, we also paid more attention to the potential metabolic and epigenetic mechanisms of psoriasis and the molecular mechanistic cascades related to its comorbidities. This review also outlined current treatment for psoriasis, especially targeted therapies and novel therapeutic strategies, as well as the potential mechanism of disease recurrence.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Clinical diversity and histopathological features of psoriasis. a, b Plaque psoriasis, c, d Guttate psoriasis, e inverse psoriasis, f erythrodermic psoriasis, g pustular psoriasis, h Nail pitting, i psoriatic arthritis, 100× (j) and 200× (k) of histopathological images of psoriasis
Fig. 2
Fig. 2
The cross-talk of extracellular cytokine pathway in psoriasis. A complex network links the essential cells and molecules in the pathogenesis of psoriasis. And the cross-talk is considered the core of the progress. On the one hand, the mutual promotion of adaptive and innate immune system produces several cytokines and maintain psoriatic hallmark features in both the dermis and epidermis. On the other hand, the keratinocytes facilitate the inflammatory mediators and enhance the expansion of local activation. Created with BioRender.com. Abbreviations: MCs mast cells, pDCs plasmacytoid dendritic cells, mature DCs mature dendritic cells, MCP Monocyte chemotactic protein, CCL20 Chemokine (C-C motif) ligand 20
Fig. 3
Fig. 3
The comprehensive view of intracellular transmission pathway in psoriasis. There are mainly two kinds of transduction way in the psoriatic cytokine. a, b The one relies on JAK-STAT and TYK2 pathways to regulate gene transcription. Specifically, IFN-α and IFN-β activate STAT1/STAT2 via JAK1 and TYK2, while IFN-γ signaling activates STAT1/STAT1 dimerize via JAK1 and JAK2.The signal of IL-12 activates STAT4/STAT4 dimerize, while IL-6, IL-23, IL-22 activates STAT3/STAT3 dimerize. c The other relies on the different cytoplasmic complexes assemble to activate NF-κB/MAPK pathway. The transduction of TNF-α, IL-17, IL-1, and IL-36 is mainly via this. Created with BioRender.com. Abbreviations: IRF9 interferon regulatory factor 9, ISRE interferon-sensitive response element, GAS IFN-γ-activated site, ISGs IFN-stimulated genes, Blimp1 B lymphocyte induced maturation protein 1, RORγt retinoic acid receptor-related orphan receptor gamma t, MyD88 myeloid differentiation factor 88, IRAK interleukin-1 receptor-associated kinases, AP1 activating protein-1, TRAF TNF receptor associated factor, Ub ubiquitin, LUBAC linear ubiquitin chain assembly complex, TRADD TNFR1-associated death domain protein, RIPK1 receptor-interacting serine/threonine-protein kinase 1, cIAP1 cellular inhibitor of apoptosis protein 1, TAK1 TGFβ-activated kinase 1
Fig. 4
Fig. 4
Metabolites in the pathogenesis of psoriasis. Compilation of the main disrupted metabolites and metabolic enzymes (red color) in psoriasis and their interconnections. Created with BioRender.com. Abbreviations: PA phosphatidic acid, DAG diacylglycerol, PE phosphatidylethanolamine, PC phosphatidylcholine, PS Phosphatidylserine, VLDL very low-density lipoproteins, HDL high-density lipoprotein, IDL intermediate-density lipoproteins, LDL low-density lipoproteins, HK2 hexokinase 2, PKM2 pyruvate kinase M2, PUFA polyunsaturated fatty acids, BCAAs branched-chain amino acids, SDH succinate dehydrogenase, GLS glutaminase, EAAs essential amino acid, ETC electron transport chain, AMPK AMP-activated protein kinase, ATP adenosine triphosphate, ADP adenosine diphosphate, AMP adenosine monophosphate, ROS reactive oxygen species
Fig. 5
Fig. 5
Epigenetic regulations in psoriasis. Environmental triggers such as smoking, medications, diet, alcohol consumption, infection, and stress can alter the expression of genes without changing the DNA sequence. This graph shows the main paradigms of epigenetic modification of psoriasis. Created with BioRender.com
Fig. 6
Fig. 6
Mechanistic models of psoriasis comorbidities. Chronic inflammatory processes directly lead to psoriatic arthritis, and they contribute to other comorbidities when coexisting with other factors. Driven by genetic factors and increased cytokines, diabetes, and IBD are likely to develop in psoriasis. Dyslipidemia, together with abnormal cytokine levels, can lead to obesity and coronary heart diseases. With a hyperactive HPA axis, psoriatic cytokines can further lead to depression. Created with BioRender.com
Fig. 7
Fig. 7
The current mechanistic model of recurrent psoriasis. In clinically resolved lesions, CD4+ TRMs remain in the dermis, while CD8+ TRMs and eLCs remain in the epidermis. With a disease trigger, eLCs release IL-23, leading to the release of IL-22 by CD4+ TRMs, thereby further inducing the hyperproliferation and inflammation of keratinocytes. CD49– CD8+ TRM cells also produce IL-17 to drive recurrent local inflammation. After interacting with the vascular addressin E-selectin, TEM cells migrate to the skin and release IL-17, thereby participating in disease recurrence. Created with BioRender.com
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