Figure 2.

Signal transduction and targets in psoriasis. (A) Fumaric acid esters (FAEs) lead to the release of NRF2, which induce and repress the expression of cytoprotective and proinflammatory cytokine genes, respectively. Also, FAEs directly inhibit NF-κB, and indirectly through induced HO-1 or inhibition of MSK1. (B) PDE4 inhibition results in increased cAMP, activating PKA and subsequent phosphorylation of the transcription factors CREB and ATF-1, which lead to increased gene expression of anti-inflammatory cytokines, and inhibition of NF-κB due to competition of the coactivators (CBP or p300). (C) TNF-α binds to TNFR, then complex 1 assembles and TAK1 activates the IKK complex and MAPKs (JNK and p38). The IKK complex phosphorylates IκBα, leading to the release of NF-κB. JNK and p38 activate AP1. Both AP1 and NF-κB increase proinflammatory gene expression. (D) IL-17A/F stimulates the IL-17 receptor complex leading to the recruitment of Act1 followed by TRAFs. The TRAF6 activates the TAK1 pathway with activation of NF-κB and AP1. TRAF2/5 recruits RNA binding proteins (eg, HuR, Arid5a) that promote mRNA stabilization of proinflammatory transcripts. Inhibition of the chaperone HSP90 results in reduced function of Act1 (E) Upon binding of IL-23 to its receptor complex, TYK2 and JAK2 activate and phosphorylate STAT3, which dimerizes and promotes the expression of proinflammatory genes and RORγt. JAKi may disrupt the signaling by targeting TYK2/JAK2. The inhibition of RORγt results in decreased Th17 differentiation and response. (F) Upon binding of piclodenoson to A₃AR, the activity of PKB/Akt is inhibited, leading to reduced NF-κB activity. (G) Tapinarof binds to AhR, the AhR-Tapinarof complex heterodimerizes with ARNT leading to downregulation of inflammatory cytokines and upregulation of skin barrier proteins. Created with BioRender.com.

Abbreviations: A₃AR, A₃ adenosine receptor; AhR, aryl hydrocarbon receptor; ARNT, AhR nuclear translocator; AP1, activator protein 1; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CBP, CREB-binding protein; C/EBPs, CCAAT/enhancer binding proteins; CREB, cAMP-response element-binding protein; FAE, fumaric acid ester; GPCR, G protein-coupled receptor; HO-1, heme oxygenase 1; HSP90, heat shock protein 90; IκBζ, inhibitor of nuclear factor kappa B zeta; IKK, inhibitor of κB (IκB) kinase complex; JAKi, janus kinase inhibitor; JNK, c-JUN N-terminal kinase; Keap1, kelch-like ECH-associated protein; MAPK, mitogen-activated protein kinases; MSK1, mitogen- and stress-activated kinase 1; NrF2, nuclear factor E2-related factor 2; PKA, protein kinase A; PKB, protein kinase B; PDE, phosphodiesterase; ROR, retinoic acid-related orphan nuclear receptor; TAP, tapinarof; TAK1, transforming growth factor-beta (TGFβ)-activated kinase 1; TNF, tumor necrosis factor; TNFR1, TNF receptor; TRAF, TNF associated factors; TYK2, tyrosine kinase 2; S1PR1, sphingosine 1-phosphate receptor 1; STAT, signaling transducers and activators of transcription.