## 2 Disease Pathogenesis Mechanism  
Psoriasis pathogenesis is governed by the interleukin (IL)-23/IL-17 signaling axis [25]. This complex signaling mechanism involves members of both the innate and adaptive immune systems. Disease onset begins with immune activation in genetically predisposed individuals following environmental triggers such as infection, medication, and smoking [26]. Another concomitant event triggering disease initiation is the loss of immune tolerance through the recognition of autoantigens, specifically antimicrobial peptides like LL-37/cathelicidin released by keratinocytes [27]. Individuals with genetic susceptibility also release self-nucleotides that can form complexes with LL-37 and are recognized by toll-like receptors (TLR7 and TLR9) on the surface of plasmacytoid dendritic cells (pDCs) [28; 29]. This binding event activates pDCs, eliciting the secretion of inflammatory mediators interferon-\(\alpha\) (IFN-\(\alpha\)) and IFN-\(\beta\) to stimulate other dermal DC subsets to produce proinflammatory mediators, such as the primary cytokine IL-23, IL-12, and tumor necrosis factor (TNF) [30]. Activated pDCs and other DC subsets present the psoriatic autoanti HL-37/cathelicidin to CD4+ and CD8+ T cells. Antigen presentation can occur within the dermis, stimulating resident memory T cells, and in the draining lymph nodes, where it activates naive T cells. At the same time, secreted IL-23 evokes the further activation and clonal expansion of IL-17- and IL-22-secreting T helper (Th)17 and Th22 cells, respectively [31]. Active Th17 cells exert their downstream effect through several cytokines IL-17, IL-26, IL-29, and TNF-\(\alpha\). They play a significant role in creating a feed-forward loop that exacerbates the disease state by recruiting other cell types. First, their key cytokine IL-17 targets keratinocytes that express IL-17 receptors, inducing the expression of CC-chemokine ligand 20 (CCL20) [32]. This chemokine attracts IL-23-producing DCs and Th17 cells, further compounding the already inflamed environment. IL-17 drives disease pathogenesis by activating psoriasis-related genes in keratinocytes via IL-22, IL-19, and IL-36 to increase epidermal hyperplasia and produce more antimicrobial peptides, including LL-37/cathelicidin [33]. IL-17 also promotes and maintains an inflammatory environment by attracting additional innate immune cell populations. In particular, circulating neutrophils aggregate at the inflamed site due to the release of neutrophil-attracting factors such as chemokine (C-X-C motif) ligand (CXCL)1/2/3/5 and CXCL8 [34]. While the IL-23/IL-17 signaling axis is pivotal in disease onset and progression, recent studies have explored the active involvement of neutrophils in psoriasis pathogenesis. Neutrophils employ a distinct mechanism called NETosis to eliminate foreign bodies. NETosis is a form of cell death in which neutrophil extracellular traps (NETs)--web-like structures composed of cytosolic proteins and decondensed DNA/RNA--are released into the surrounding environment [35; 36]. Upon receiving inflammatory stimuli, recruited neutrophils actively form NETs within psoriatic lesions. Notably, the severity of psoriasis correlates with the quantity of NETs in blood samples [37]. These NETs are abundant in LL-37 and RNA. LL-37 can form complexes with RNA, facilitating RNA's uptake by neutrophils. This process subsequently activates TLRs and leads to the secretion of IL-8, a neutrophil chemotactic factor that recruits additional neutrophils to the lesion site [38]. Intriguingly, the same complex can induce neutrophils to release more NETs, thereby propagating the inflammatory cycle [39]. Thus, in the IL-23/IL-17 disease model, dermal DCs release IL-23, which eventually induces Th17 cell activation and proliferation. Th17 cells produce proinflammatory cytokines to target keratinocytes, which sustains and enhances the chronic inflammatory state by generating additional IL-23, as well as other proinflammatory cytokines, chemokines, S100 family proteins, and antimicrobial peptides.