# Sporiasis Pathogenesis and Treatment
## 2 Pathogenesis
### Main Cytokines and Cell Types in Plaque Psoriasis  
Disturbances in the innate and adaptive cutaneous immune responses are responsible for the development and sustainment of psoriatic inflammation [53; 54]. An activation of the innate immune system driven by endogenous danger signals and cytokines characteristically coexists with an autoinflammatory perpetuation in some patients, and T cell-driven autoimmune reactions in others. Thus, psoriasis shows traits of an autoimmune disease on an (auto)inflammatory background [55], with both mechanisms overlapping and even potentiating one another. The main clinical findings in psoriasis are evident at the outermost layer of the skin, which is made up of keratinocytes. However, the development of the psoriatic plaque is not restricted to inflammation in the epidermal layer, but rather is shaped by the interaction of keratinocytes with many different cell types (innate and adaptive immune cells, vasculature) spanning the dermal layer of the skin. The pathogenesis of psoriasis can be conceptualized into an initiation phase possibly triggered by trauma (Koebner phenomenon), infection, or drugs [53] and a maintenance phase characterized by a chronic clinical progression (see Figure 5). Figure 4: Histopathology of psoriasis. (**A**) Psoriasis vulgaris characteristically shows acanthosis, parakeratosis, and dermal inflammatory infiltrates. (**B**) In pustular psoriasis, acanthotic changes are accompanied by epidermal predominantly neutroph infiltrates, which cause pustule formation. Figure 5: The pathogenesis of psoriasis. It is well known that dendritic cells play a major role in the initial stages of disease. Dendritic cells are professional antigen-presenting cells. However, their activation in psoriasis is not entirely clear. One of the proposed mechanisms involves the recognition of antimicrobial peptides (AMPs), which are secreted by keratinocytes in response to injury and are characteristically overexpressed in psoriatic skin. Among the most studied psoriasis-associated AMPs are LL37, \(\beta\)-defensins, and S100 proteins [56]. LL37 or cathelicidin has been attributed a pathogenic role in psoriasis. It is released by damaged keratinocytes, and subsequently forms complexes with self-genetic material from other damaged cells. LL37 bound to DNA stimulates toll-like receptor (TLR) 9 in plasmacytoid dendritic cells (pDCs) [57]. The activation of pDC is key in starting the development of the psoriatic plaque, and is characterized by the production of type I IFN (IFN-\(\alpha\) and IFN-\(\beta\)). Type I IFN signaling promotes myeloid dendritic cells (mDC) phenotypic maturation, and has been implicated in Th1 and Th17 differentiation and function, including IFN-\(\gamma\) and interleukin (IL)-17 production, respectively [58; 59; 60]. Whilst LL37-DNA complexes stimulate pDCs through TLR9, LL37 bound to RNA stimulates pDCs through TLR7. In addition, LL37-RNA complexes act on mDCs via TLR8 [56; 57]. Activated mDCs migrate into draining lymph nodes and secrete tumor necrosis factor (TNF)-\(\alpha\), IL-23, and IL-12, with the latter two modulating the differentiation and proliferation of Th17 and Th1 cell subsets, respectively. Furthermore, slan\({}^{+}\) monocytes, which are important pro-inflammatory cells found in psoriasis skin lesions, respond to LL37-RNA activation by secreting high amounts of TNF-\(\alpha\), IL-12, and IL-23 [61]. The activation of the adaptive immune response via the distinct T cell subsets drives the maintenance phase of psoriatic inflammation [62]. Th17 cytokines, namely IL-17, IL-21, and IL-22 activate keratinocyte proliferation in the epidermis. The inflammatory milieu activates keratinocyte proliferation via TNF-\(\alpha\), IL-17, and IFN-\(\gamma\). Keratinocytes are also activated by LL37 and DNA, and greatly increase the production of type I IFNs [57]. Furthermore, they participate actively in the inflammatory cascade through cytokine (IL-1, IL-6, and TNF-\(\alpha\)), chemokine, and AMP secretion.