# New Treatment Addressing the Pathogenesis of Psoriasis
## 2 Pathogenesis of Psoriasis  
### 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 \(\beta\)-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]. The defensins are cationic microbicidal peptides separated into three categories; defensins \(\alpha\), \(\beta\), and \(\theta\)[8]. The \(\alpha\)-defensins are further separated into six subtypes designated as human neutrophil peptides (HNPs) 1-6, and HNPs 1-3 are present in the scales of psoriatic lesions [9]. The \(\beta\)-defensins \begin{table}
\begin{tabular}{c c c c} \hline \hline
**Name** & **Target** & **Stage** & **Dosage Form** \\ \hline VTP-43742 & ROR\(\gamma\)t inhibitor & Phase 2 & Oral \\ GSK2981278 & ROR\(\gamma\) inverse agonist & Phase 1 & Topical \\ BI 655130 & IL36-receptor antagonist & Phase 1 & Intravenous \\ Todacitinib & JAK inhibitor & Phase 3 & Oral \\ Baricitinib & JAK1/JAK2 inhibitor & Phase 2 & Oral \\ BMS-986165 & TYK2 inhibitor & Phase 2 & Oral \\ PF-06700841 & TYK2/JAK1 inhibitor & Phase 2 & Topical \\ Ponesimod & S1 PR1 agonist & Phase 2 & Oral \\ KD025 & ROCK2 inhibitor & Phase 2 & Oral \\ Tapinarof & AhR agonist & Phase 2 & Topical \\ \hline \hline \end{tabular}
\end{table} 
Table 2: Summary of new treatments under clinical trials for psoriasis. 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; S1 PR1: sphingosine-1-phosphate receptor 1; ROCK2: Rho-associated kinase 2; IL: interleukin; AhR: aryl hydrocarbon receptor. are separated into four subtypes designated as human \(\beta\)-defensins (hBDs) 1-4. TNF\(\alpha\) and IFNvinduce hBDs 2 and 3, which are highly present in the psoriatic scales, and IL17A and IL22 also induce hBDs 2 in keratinocytes [6]. The role of defensins in the pathogenesis of psoriasis is not yet fully understood [10]. The S100 proteins comprise a family of low-molecular-weight (9-13 kDa) proteins [11]. S100A7 (psoriasin), S100A8 (calgranulin A), S100A9 (calgranulin B), S100A12 (calgranulin C), and S100A15 are highly expressed in psoriasis [8]. The combination of IL22, IL17A, IL17F, and keratinocytes synergistically induced the expression of \(\beta\)-defensin 2, S100A9, S100A7, and S100A8 [12]. S100A7 (psoriasin) is reported as a potent and selective chemotactic inflammatory protein for T cells and neutrophils in psoriasis [13]. 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]. LL37 bound to RNA stimulates pDCs through TLR7 and LL37-RNA complexes act on myeloid DCs (mDCs) through TLR8 [7,10,16]. Activated mDCs migrate into draining lymph nodes and produce TNF\(\alpha\), IL23, and IL12. Slan+ monocytes also respond to LL37-RNA activation and produce TNF\(\alpha\), IL23, and IL12 (Figure 1) [17]. IL23 and IL12 induce naive T cell to Th17 and Th1 cell subsets, respectively [7]. An in silico docking study by [PERSON] et al.