New Treatment Addressing the Pathogenesis of Psoriasis

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.


Introduction
Psoriasis is a chronic inflammatory cutaneous disease characterized by the formation of scaly, indurated, erythematous plaques. Psoriasis has three principal histologic features: epidermal hyperplasia; dilated, prominent blood vessels in the dermis; and an inflammatory infiltrate of leucocytes, predominantly into the dermis [1]. Not only limited to the skin, psoriasis also affects joints and nails. Psoriasis is mainly divided into three clinical types: psoriasis vulgaris, psoriatic arthritis, and generalized pustular psoriasis (GPP). Psoriasis often coexists with other systemic disorders including obesity, hypertension, hyperlipidemia, diabetes, metabolic syndrome, cardiovascular disease, which is called psoriatic march or inflammatory march, and chronic kidney disease [2,3]. Psychiatric disorders, psychosocial distress such as depression are also seen in psoriatic patients [4].

Rho-Associated Kinase (ROCK2) Inhibitor
Rho family kinases, consisting of ROCK1 and ROCK2, are serine-threonine kinases activated by Rho GTPases and mediate the phosphorylation of downstream targets in cells [110,111]. KD025 is adenosine triphosphate (ATP) competitive and 100-fold more selective for the ROCK2 isoform when compared with ROCK1, with no significant activity against 300 other intracellular kinases and surface

AMPs
AMPs are composed of 12-50 amino acids, have positive charge, amphipathic structure, and play important roles in host protection by killing pathogenic microorganisms including bacteria, protozoa, fungi, and viruses [5,6]. AMPs also affect host inflammatory responses by acting as chemotactic agents, angiogenic factors, and regulators of cell proliferation in vertebrates [6]. In psoriasis, certain AMPs, including β-defensins, S100 proteins, and cathelicidin, are highly expressed and secreted by keratinocytes, neutrophils, and macrophages in response to injury and cytokine stimulation ( Figure 1) [7].
Cathelicidin LL37 is the C-terminal peptide fragment derived from hCAP18 [14]. Plasmacytoid DCs (pDCs) recognize self-DNA through TLR9 and LL37 is the key factor that mediates pDCs' activation in psoriasis [15]. Furthermore, keratinocytes exposed to LL37 and self-DNA produce type I IFN, which is related to the development of psoriasis ( Figure 1) [16].
An in silico docking study by Mabuchi et al. confirmed that multiple 9-mer peptides derived from LL37 exhibit high binding affinities for HLA-C*06:02 molecules, and they proposed a mechanism for the interaction between LL37 HLA-C*06:02 complexes and T cells via T-cell receptors [18].

A Disintegrin and Metalloprotease Domain Containing Thrombospondin Type 1 Motif-Like 5 (ADAMTSL5)
The melanocyte-derived protein ADAMTSL5 has been identified as an autoantigen [19]. Intra-epidermal CD8 T cells recognize ADAMTSL5 on melanocytes in association with HLA-C*06:02 [19]. Keratinocytes produce ADAMTSL5 with IL17 stimulation and CXCL1, which is a neutrophil chemoattractant and melanocyte growth factor, induce ADAMTSL5 expression [19]. In psoriasis, the number of melanocytes is increased and T cells including cytotoxic T cells co-localize with these melanocytes [20]. However, it is suggested that melanocytes are likely targets of the non-cytotoxic CD8+ T cell-mediated autoimmune response because the number of melanocytes increase, but melanocytes do not show signs of cell death in psoriasis [21]. The ADAMTSL5 expression pattern mirrors the pattern of T cell infiltration and DC aggregation in the superficial dermis in psoriasis, which is similar to LL37 [22]. The expression of ADAMTSL5 and LL37 with DCs, neutrophils, macrophages, and T cells in psoriasis significantly decreases after treatment of IL17 or TNFα blocker [23,24]. This suggests that ADAMTSL5 and LL37 are presented to autoreactive CD4+ T cells by HLA-class II molecules and to CD8+ T cells by HLA-Cw6*02, which are expressed on the surface of antigen-presenting cells within the dermal lymphoid tissue structures [19,24]. A synthetic ADAMTSL5 peptide increases the frequency of CD8 T cells expressing IL17A and IFN7among the peripheral blood mononuclear cells in psoriasis patients, but the same effect is not found in healthy individuals [19].
Under healthy conditions, cDCs are also associated with maintaining immune tolerance through depletion of autoimmune T cells, expressing anti-inflammatory cytokines and inhibitory receptors including IL10, transforming growth factor (TGF)β, and IL27 and prompting the homeostasis of regulatory T cells (Tregs) [37,38]. Dysregulation of this tolerance mechanism has been found in many autoimmune diseases such as psoriasis [39,40]. By inducing tolerogenic DCs, α-melanocyte-stimulating hormone ameliorates psoriasis by promoting Treg expansion and downregulating the proliferation of human and murine Th17 cells and cytokine production [41]. cDCs are activated by multiple cytokines such as IL6, TNFα, IFNα, and also LL37-RNA complexes [25]. Activated cDCs produce a mass of inflammatory cytokines such as IL12 and IL23, which are key mediators in psoriasis [25].
The number of LCs in psoriasis is likely to be variable, as it can increase [42], decrease [43], or remain the same [44]. Subsequent experiments demonstrated that increased expression of IL17 is responsible for impaired LC migration in the uninvolved skin of patients with psoriasis [45]. Recent studies demonstrated that activation of the STAT3 pathway in keratinocytes and TLRs in LCs can induce LCs to produce IL23 and monocyte-derived LCs (mLCs) exhibit a more powerful ability to secrete IL23 when compared with resident LCs (rLCs) (Figure 1) [44,46]. Furthermore, LCs are in close contact with T cells in patients who achieved almost complete remission after anti-TNFα treatment, and they retain a higher capacity for secreting IL23 when compared with healthy volunteers following TLR7/8 stimulation in vitro [25]. This emphasizes that LCs may be associated with recurrence of psoriasis, although this ability is to a small extent comparable with progressive stage psoriasis [44]. Recent studies have shown that LCs indeed produce IL23, and the close proximity to pathogenic T cells suggests that LCs may as be associated with the pathogenesis of psoriasis as other DCs [25]. However, a negative regulatory role of LCs has been observed. The function of LCs in psoriasis varies, and LCs may function as the gate that regulates the degree of inflammatory responses in the disease [25].

Aryl Hydrocarbon Receptor (AhR)
The AhR is a cytosolic ligand-activated receptor and transcription factor, which is widely expressed in the skin cells [57,58]. Endogenous and exogenous molecules and dioxins are known as ligands of AhR [57,58]. AhR activation induces oxidative stress through CYP1A1 and neutralizes oxidative stress through the nuclear factor-erythroid 2-related factor-2 (NRF2) transcription factor [59]. Furthermore, AhR regulates the balance of the Th17/22 system, which is important for developing psoriasis [59]. AhR agonists decreased IL-23 receptor, Th17 master transcription factor retinoic acid-related orphan receptor C (RORC) and the number of Th17 cells [60].
In addition, AhR in cutaneous vascular endothelial cells (VECs) also plays an important role in the development of psoriasis [61]. Zhu et al. found that AhR in cutaneous VECs downregulates neutrophil recruitment through adhesion molecule ICAM-1 in psoriasis using specific AhR knockout mice ( Figure 1) [61].

Retinoids
Retinoids are derivatives of vitamin A and bind to nuclear receptors, retinoic acid receptors, and retinoid X receptors, which regulate gene transcription such as IL6 [6]. Retinoids induce keratinocyte differentiation and reduce epidermal hyperplasia, leading to a slowing of cell reproduction [62]. Etretinate, which is a second-generation retinoid, is used in Japan, and acitretin, which is an active metabolite of etretinate, has a shorter half-life, and is eliminated more rapidly than etretinate, is used in many countries [62]. The Psoriasis Area Severity Index 75 (PASI75) response to acitretin 25, 35, and 50 mg/day groups at week 12 were 47%, 69%, and 53%, respectively [63]. The main adverse effects were dry mouth, cheilitis, pruritus, teratogenicity, and elevations in serum lipid and liver enzymes [62,63].

Methotrexate
Methotrexate (MTX) inhibits dihydrofolate reductase (DHFR), an enzyme that participates in the tetrahydrofolate synthesis. MTX induces inhibition of purine, methionine, and thymidylate synthesis and inhibits DNA synthesis [64]. Low-dose MTX may have anti-inflammatory effects, including increased adenosine levels, and modulates immune cells [64]. The PASI75 response to MTX at week 12 was 45.2% [65]. The main adverse events were nausea, vomiting, mouth ulcers, upper respiratory infection, abnormal liver function tests, and interstitial lung disease [65].

Cyclosporine A
Cyclosporine A (CyA) is a calcineurin inhibitor. CyA forms a complex with cyclophilin and blocks phosphatase activity of calcineurin and decreases the production of inflammatory cytokines including in T cells [6,66]. The PASI75 response to CyA 5 mg/kg and 2.5 mg/kg at week 10 to 16 was 50-97% and 28-85%, respectively [66]. The main adverse effects are nephrotoxicity, hepatotoxicity, hypertension, an increased risk of infection, and lymphoma [66].

Apremilast
Apremilast is a selective inhibitor of the enzyme phosphodiesterase 4 (PDE4), which breaks down cyclic adenosine monophosphate (cAMP). PDE4 is the main enzyme in immune cells such as T cells, macrophages, and epithelial cells [6]. Through PDE4 inhibitors, the level of cAMP increases and cAMP downregulates proinflammatory cytokine including TNFα and upregulates anti-inflammatory cytokine including IL10. The PASI75 response to apremilast at week 12 was 33.1% [67]. The main adverse events are diarrhea, vomiting, and depression [67].

TNFα Inhibitors
Infliximab, adalimumab, and certolizumab pegol are currently available for the treatment of psoriasis as TNFα inhibitors. Certolizumab pegol is an Fc-free, PEGylated TNFα inhibitor. It does not bind the neonatal Fc receptor for IgG (FcRn) and consequently shows minimal placental transfer from mothers to infants [68]. At week 10, PASI 75 response rates for infliximab at 5 mg/kg dose were 80% [69]. At week 16, PASI 75 response rates for adalimumab at 40 mg after an initial 80 mg dose were 80% [70]. At week 16, PASI 75 response rates for certolizumab pegol at 400 mg were 80.1% [71]. The main severe adverse events were reactivation of hepatitis B and C, tuberculosis, drug-induced lupus, demyelinating central nervous system disorders, and paradoxical reactions such as psoriasis and psoriasiform skin lesions [69,70].

RORγt Inhibitors
Retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt or RORc2) is a key transcription factor for Th17 cell differentiation [4]. Inhibiting RORγt activity is thought to be a promising strategy for the treatment of psoriasis [4]. A phase 2a clinical trial of RORγt inhibitor VTP-43742 in psoriatic patients was conducted [79]. A significant reduction in the psoriasis area severity index (PASI) score relative to the placebo was observed in the 350 mg (24%) and 700 mg (30%) dose groups [79]. However, reversible transaminase elevations were observed in the 700 mg dose group in four patients. Because of this liver toxicity, the initially planned third clinical trial of VTP-43742 was discontinued [79]. Although the phase 1 clinical trial of GSK2981278 ointment (selective RORγ inverse agonist) showed a lack of efficacy, new topical RORγt inhibitors may be a potential candidate for the treatment of psoriasis [80,81].

IL36 Receptor Antagonist
IL36 is an IL1 superfamily member and plays an important role for recruiting and activating neutrophils and Th17 cells in psoriasis [82]. Loss-of-function mutations have been found in IL36RN, which encodes an IL36-receptor antagonist, in some GPP patients [83]. In the phase 1 clinical trial, an intravenous single dose of BI 655130, a monoclonal antibody against the interleukin-36 receptor showed good efficacy regardless of the presence of the IL36RN mutation over a 20-week period [83].

Janus Kinase (JAK) Inhibitors
Type 1 and 2 cytokine receptors strongly depend on the JAK and STAT pathways [84]. The JAK family is intracellular protein tyrosine kinase and includes JAK1,2,3, and TYK2, and the STAT family includes STAT1, 2, 3, 4, 5a, 5b, and 6 [84]. The functions of each JAK and STAT are different [84]. The IL23 receptor, which is important in psoriasis, is associated with JAK2, TYK2, and STAT3 [84]. JAK inhibitors are currently being tested in clinical trials for the treatment of psoriasis (Table 2) [85].
The TYK2 inhibitor BMS-986165, which is a more selective JAK inhibitor than first-generation candidates, showed efficacies of 75% (12 mg daily), when compared to 7% in the placebo group in terms of PASI75 response at week 12 of treatment in a phase 2 clinical trial [85].
The TYK2/JAK1 inhibitor PF-06700841 directly suppresses TYK2-dependent IL12 and IL23 signaling, and JAK1-dependent signaling in cells such as T cells and keratinocytes [92]. PF-06700841 improves clinical symptoms of chronic plaque psoriasis by inhibiting proinflammatory cytokines that require TYK2 and JAK1 for signal transduction [92]. Topical PF-06700841 is now under investigation in a phase 2 trial [93].

Sphingosine-1-Phosphate (S1P) Agonist
Sphingosine is created from ceramide, which is composed of membrane lipids, through ceramidase [94]. S1P is created from sphingosine through sphingosine kinase [94]. S1P is a lipid mediator and associated with cellular proliferation, survival, migration, inflammation, immune cell trafficking, angiogenesis, vascular integrity, and adhesion in the immune and vascular systems [95]. S1P acts on five specific G protein-coupled receptors named S1P receptor (S1PR)1-5 [95]. S1PR1 is expressed on lymphocytes and controls their egress from thymus and secondary lymphoid organs [96,97]. S1PR1 modulators induce internalization of this receptor and the majority of circulating lymphocytes are sequestered in lymph nodes, decreasing peripheral lymphocyte counts and trafficking of lymphocytes to peripheral tissues ( Figure 2) [98,99]. Furthermore, it has been reported that S1P inhibits the growth of epidermal cells, induces differentiation of keratinocytes, and shows antiproliferative and anti-inflammatory effects in mouse models of psoriasis [100][101][102][103][104].
Ponesimod (ACT-128800) is an orally selective S1PR1 agonist, which blocks the egress of T cells from lymphoid organs [105,106]. Ponesimod is excreted within 1 week after discontinuation, and this rapid elimination is beneficial in cases including vaccinations and pregnancy [107,108].

Rho-Associated Kinase (ROCK2) Inhibitor
Rho family kinases, consisting of ROCK1 and ROCK2, are serine-threonine kinases activated by Rho GTPases and mediate the phosphorylation of downstream targets in cells [110,111]. KD025 is adenosine triphosphate (ATP) competitive and 100-fold more selective for the ROCK2 isoform when compared with ROCK1, with no significant activity against 300 other intracellular kinases and surface receptors [111,112]. Recent studies showed that oral administration of a selective ROCK2 inhibitor (KD025) in healthy subjects decreases IL17 and IL21 secretion induced by ex vivo stimulation (Figure 2) [111]. Moreover, targeted ROCK2 inhibition shifted the balance between proinflammatory and immunosuppressive T-cell subsets through concurrent regulation of STAT3/STAT5 phosphorylation [113,114].
In the phase 2 clinical trial, KD025 significantly reduced both IL17 and IL23 levels. KD025 also decreased epidermal thickness, K16 expression, and T-cell infiltration in the skin [114]. In addition, the PASI50 response to KD025 (200 mg twice daily) at week 12 was 71% [114]. In contrast, KD025 significantly increased levels of the immunosuppressive cytokine IL10, but TNFα and IL6 levels were not changed [114]. ROCK2 expression is induced during Th17-skewing conditions and regulates IL17 secretion through a STAT3/IRF4/RORγt-dependent mechanism in mice and humans [111,115].
In the phase 2 clinical trial, the PASI75 response to topical tapinarof at week 12 was 65% (1% twice daily) and 56% (1% once daily) when compared to 16% (twice daily) and 5% (once daily) for the placebo. The most frequently reported adverse events were folliculitis and contact dermatitis in the tapinarof groups [118]. Therefore, topical tapinarof is efficacious in the treatment of psoriasis.

Conclusions
In this review, we summarized new insights regarding the pathogenesis of psoriasis, as it relates to AMPs, DCs, the IL23/IL17 axis, and AhR. Moreover, we summarized new treatments, including JAK inhibitors, ROCK inhibitors, S1P agonists, and AhR agonists. Some of these treatments are currently undergoing clinical trials and are expected to be on the market. To improve the quality of life of psoriatic patients, the choice of available treatments is now increasing.