# Soriasis: From Pathogenesis to Pharmacological and Nano-Technological-Based Therapeutics
## 1 Introduction  
Soriasis is an inflammatory skin disorder that mainly depends on genetic predisposition and ageing. However, there are some environmental risk factors, such as trauma (e.g., Koebner phenomenon), infection, and drugs, that have been proposed to influence the development of this inflammatory skin disease. This pathology affects around 2% of the population worldwide, but it shows some variability, depending on the type of skin [1]. In this sense, in Caucasian and Scandinavian people, it increases its prevalence, rising until 11% of their population is affected [2]. Several types of psoriasis have been identified, depending on how it affects the patient. The majority of psoriasis cases correspond to psoriasis vulgaris or plaque-type psoriasis (almost 90%). Plaque-type psoriasis is easily recognised by the pruritic plaques covered in silvery scales [3]. Innate and adaptative immune responses are responsible for the development of psoriatic inflammation, while innate immune responses are more significant in plaque-type psoriasis [4]. One of themost accepted mechanisms involves an overexpression of antimicrobial peptides in psoriaticic skin, acting as a trigger and a continued maintenance phase [5]. Some of the most studied hallmarks of psoriasis are LL-37, \(\beta\)-defensins, and S100 proteins [6]. In the earlier phase, there is an abnormal decease of LL-37 and different antimicrobial peptides from keratinocytes in stress conditions, such as physical injury. LL-37 is released by damaged keratinocytes and forms complexes with genetic material from damaged cells around the keratinocyte. LL-37 has been recognised as a participant in the pathogenesis of the psoriasis, due to the boundaries with DNA-stimulating toll-like receptor 9 in plasmacytoid dendritic cells [7]. There are two ways in which LL-37 affects the activation of plasmonic dendritic cells. On the one hand, the stimulated production of type I IFN, which promotes phenotypic maturation of myeloid dendritic cells, has an important role in Th1 and Th17 differentiation and function [6; 7; 8]. Th-17 cells are special populations of CD4+ T cells that produce IL-17, IL-22, IL-21, TNF-\(\alpha\), and other cytokines and express lineage specific transcription factor Retinoic acid receptor-Related Orphan receptor (RORC) [9; 10]. The family of Th-17 cells includes several cell types, all of them expressing ROR-\(\gamma\)t and IL-23R. In a study published in 2018, the authors determined the mRNA expression level of RORC in patients with psoriasis and found significantly higher gene expression of RORC in patients with psoriasis than in control patients, thus concluding that Th-17 plays a role in the pathogenesis of the disease [11]. ROR\(\gamma\)T and its isoform, ROR, are encoded by a single gene called Rorg (also known as Rorc). Both isoforms use the last 9 exons (exons 3-11) of the Rorg gene, but the other exons used by them are different. Consequently, the ROR\(\gamma\)T mRNA differs from that of ROR in the first 100 nt, which translates into distinct N-terminal amino acid sequences [12]. Expression of ROR\(\gamma\)t is not only confined to Th17 cells, but also regulates cytokine production in other cell types, such as CD8+Tc17 cells, invariant natural killer T cells, ILC3, and \(\gamma\)8 T-cells [13]. All of these contribute to autoimmune tissue inflammation. Moreover, it has been found that ROR\(\gamma\)-deficient mice show diminished Th17/IL-17 responses and are protected against autoimmune inflammatory diseases, such as psoriasis-like skin inflammation [14]. Pharmacological modulation of ROR\(\gamma\)t by low molecular weight inhibitors is therefore an attractive approach to inhibit the proinflammatory IL-17/IL-23 axis. Given the fact that it is a nuclear hormone receptor, the activity of ROR\(\gamma\)t is regulated in a ligand-dependent manner. Therefore, numerous inhibitors targeting the ligand binding domain (LBD) of ROR\(\gamma\)t have been reported recently.