New Treatment Addressing the Pathogenesis of Psoriasis

Abstract

Psoriasis is an immune cell-mediated inflammatory skin disease. The interleukin (IL)23/IL17 axis plays an important role in the development of psoriasis. The effectiveness of biologic treatments such as tumor necrosis factor (TNF)α inhibitors (infliximab, adalimumab, certolizumab pegol), IL23 inhibitors (ustekinumab, guselkumab, tildrakizumab, risankizumab), and IL17 inhibitors (secukinumab, ixekizumab, brodalumab) have verified these findings. Immune-related cells such as dendritic cells (DCs) and macrophages, in addition to Toll-like receptors and cytokines such as interferon (IFN)α, TNFα, IFNɤ, IL12, IL22, IL23, and IL17, are related to the pathogenesis of psoriasis. Here, we first review new insights regarding the pathogenesis of psoriasis, as it relates to DCs, Langerhans cells, macrophages, the signal transducer and activator of transcription 3 pathway, and aryl hydrocarbon receptor in cutaneous vascular endothelial cells. Based on these findings, we summarize currently available oral treatments and biologics. Furthermore, we describe a new treatment option including Janus kinase inhibitor, tyrosine kinase 2 inhibitor, modulator of sphingosine 1-phosphate receptor 1, and Rho-associated kinase 2 inhibitor.

Keywords: Janus kinase inhibitor; Rho-associated kinase 2 inhibitor; aryl hydrocarbon receptor; dendritic cells; new treatment; pathogenesis; psoriasis; sphingosine 1-phosphate receptor 1.

Figure 1

Summary of pathogenesis of psoriasis. KCs produce AMPs such as β-defensins, S100 proteins, and cathelicidin. LL37 and ADAMTSL5 are considered to be as autoantigens. LL37–DNA complexes stimulate pDCs, and pDCs secrete IFNα. LL37-RNA complexes stimulate mDCs and mDCs produce TNFα, IL23, and IL12. IL23 stimulates Th17 cells and Th17 cells produce IL17 and IL22 through the JAK-STAT pathway. LCs also secrete IL23 and stimulate Th17 cell. AhR in cutaneous VECs downregulate neutrophil recruitment. KC: keratinocyte; AMP: antimicrobial peptides; ADAMTSL5: A disintegrin and metalloprotease domain containing thrombospondin type 1 motif-like; pDC: plasmacytoid dendritic cell; IFN: interferon; mDC: myeloid dendritic cell; iDC: inflammatory dendritic cell; TNF: tumor necrosis factor; IL: interleukin; JAK: Janus kinase; STAT: signal transducer and activator of transcription; LC, Langerhans cell; AhR: aryl hydrocarbon receptor; VEC: vascular endothelial cell; Neu: neutrophil; HLA: human leukocyte antigen.

Figure 2

Summary of new treatment. (a) JAK inhibitor blocks the JAK-STAT signal pathway in Th17 cells. (b) Ponesimod, a selective S1P1 agonist, induces sequestration of lymphocytes into lymph nodes and decreases peripheral lymphocyte counts and trafficking of lymphocytes to peripheral tissues. (c) KD025, ROCK2 inhibitor reduces IL17 secretion in Th17 cells. (d) Tapinarof, AhR agonist reduces IL17 and IL22 in Th17 cells. JAK: Janus kinase; STAT: signal transducer and activator of transcription; S1PR1: sphingosine-1-phosphate receptor 1; ROCK2: Rho-associated kinase 2; IL: interleukin; AhR: aryl hydrocarbon receptor.