# New Treatment Addressing the Pathogenesis of Psoriasis
## 2 Pathogenesis of Psoriasis
### DCs  
The skin contains a complex network of DCs mainly composed of epidermal Langerhans cells (LCs), bone-marrow-derived dermal conventional DCs (cDCs), pDCs, and inflammatory DCs (iDCs) [25]. As the prominent cellular source of IFN\(\alpha\), TNF\(\alpha\), IL12, and IL23, DCs play an important role in psoriasis [25]. pDCs originate in the bone marrow and migrate to the skin under pathologic conditions [25]. pDCs recognize viral nucleic acids and produce large amounts of type I IFNs in response to endosomal Toll-like receptors (TLRs), such as TLR7 and 9 [26, 27, 28, 29]. Inappropriate recognition of self-nucleic acids by pDCs results in producing IFN\(\alpha\) and initiating psoriatic inflammation [29, 30]. The AMPs such as LL37, human \(\beta\)-defensin (hBD) 2, hBD3, and lysozyme are able to condense self-DNA or RNA into particles that are endocytosed by pDCs, leading to activation of TLR7, 8, and 9 in psoriasis [29; 30; 31]. In psoriatic inflammation, IFN\(\alpha\) is considered to act as an upstream cytokine along the IL23/IL17 axis [32]. IFN\(\alpha\) strongly activates immature cDCs to secrete IL12, IL15, IL18, and IL23 [33]. In addition, IFN\(\alpha\) induces the rapid differentiation of human monocytes into iDCs and polarizes CD4+ T cells into Th1 and Th17 cells [34; 35]. Furthermore, IFN\(\alpha\) also enhances the reaction to IL22 on epidermal keratinocytes by upregulating IL22 receptor expression [36]. 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)\(\beta\), 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, \(\alpha\)-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, TNF\(\alpha\), IFN\(\alpha\), 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]. iDCs are considered to be derived from monocytes and have the ability to polarize T cells to Th1, Th2, and Th17 and produce cytokines such as IL1, IL6, TNF\(\alpha\), IL12, IL22, and IL23 [27]. In psoriasis, TNF\(\alpha\), and inducible nitric oxide synthase (iNOS)-producing DCs (Tip-DCs) and 6-sulfo LacNAc DCs (slanDCs) are reported as iDCs, and they induce T cells to secrete IL17, IL22, TNF\(\alpha\), and IFN\(\chi\)[14]. SlanDCs are also stimulated by TNF\(\alpha\) and produce IL12, IL23, IL18, and IL6 [17]. 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-TNF\(\alpha\) 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].