Psoriasis is a chronic inflammatory skin disease characterized by deregulated activation of immune cells and keratinocytes (1, 2). The pathophysiology of psoriasis includes hyperproliferation and abnormal differentiation of epidermal keratinocytes and dermal infiltration of multiple immune cells (1, 2). The interplay between immune cells and keratinocytes is crucial for the initiation and progression of psoriasis (3, 4) although detailed molecular mechanisms underlying the development of psoriasis need to be explored. Dendric cells (plasmacytoid and myeloid dendritic cells) contribute to the early stages of psoriasis, and activation of T cells, such as Th1, Th17, and Th22, plays a critical role during the chronic maintenance phase (1, 2).
Furthermore, keratinocytes reportedly participate in the initiation and progression of psoriasis (5, 6). Upon skin damage, keratinocytes secrete self-nucleotides and antimicrobial peptides, activating plasmacytoid dendritic cells (7), and release multiple proinflammatory cytokines via the toll-like receptor (TLR) 3 pathway (8, 9). During psoriasis progression, keratinocytes recruit immune cells by secreting chemokines and enhance inflammation by producing multiple inflammatory mediators (5, 6). Topical application of imiquimod (IMQ), a TLR7 agonist, has been reported to induce psoriasis-like lesions in mouse skin via the interleukin (IL)-23/IL-17 axis (10), which is used as a mouse model for psoriasis. Aldara is an IMQ cream formulation and frequently applied topically (11).
Retinoic acid receptor-related orphan receptor α (RORα) plays a diverse role in physiology, including brain development, circadian rhythm, metabolic pathways, and inflammation, by regulating transcription programs as transcription factors or corepressors (12). Although RORα was initially considered an orphan nuclear receptor, cholesterol, cholesterol sulfate, and other cholesterol derivatives have been suggested as putative endogenous ligands (13, 14). Subsequently, many natural and synthetic ligands have been developed to modulate RORα activity (15). RORα is highly expressed in the skin epithelium, with a potential role in promoting keratinocyte differentiation (16, 17). Furthermore, cholesterol sulfate was found to induce the expression of filaggrin, a differentiation marker protein, in human keratinocytes by activating RORα (18). SR1001, a synthetic inverse RORα/γ agonist, can alleviate inflammation, atopic dermatitis-related symptoms, and acute irritant dermatitis in mouse models (19). In the present study, we investigated the role of RORα in psoriasis progression using a mouse model with specific deletion of the
As no systematic analysis regarding the contribution of RORα in skin physiology has been reported, we established a mouse model containing a keratinocyte-specific
We performed immunostaining to detect
Given that epithelial cell hyperproliferation is a typical symptom of psoriasis, we examined keratinocyte proliferation in an IMQ-induced psoriasis-like condition. Keratinocyte proliferation was examined by comparing the epidermal expression of Ki67, a cell proliferation marker protein, in the dorsal skin of
We next addressed the inflammatory status of keratinocytes, given that chronic inflammation is another key factor in psoriasis progression. We isolated primary keratinocytes from the skin of newborn
Psoriasis is an autoimmune skin disease that involves T cell-mediated sustained inflammation during the chronic disease phase (1, 2). Epidermal keratinocytes reportedly play a pivotal role in the progression of psoriasis (5, 6). RORα, along with RORγ, has been identified as a key transcription factor in Th17 differentiation, a critical contributor to psoriasis progression (23). Moreover, a synthetic inverse RORα/γ agonist was found to be effective in treating atopic dermatitis and acute irritant dermatitis in mouse models (19).
It has been reported that RORα controls the expression of some keratinocyte genes, including keratin 1, keratin 10, involucrin, loricrin and filaggrin, and promotes keratinocyte differentiation in human keratinocytes (16). We also detected the decreased expression of certain genes in
STAT3 is considered a crucial transcription factor in the development and progression of psoriasis in terms of the activation of immune cells and keratinocytes (24). STAT3 contributes to the differentiation and activation of Th17 cells, as well as acts as a transcription factor in the response of keratinocytes to cytokines from immune cells (24). Additionally, activation of STAT3 is well known as the cause of hyperproliferation of keratinocytes in psoriasis (24). STAT3 inhibitor has been reported to reduce proliferation of normal human keratinocytes through downregulation of c-Myc and cyclin D1, and STAT3 inhibitor has been considered as a therapeutic target for the treatment of psoriasis (25). It has been reported that constitutive expression of active Stat3 in keratinocytes of mouse skin can induce a psoriasis-like skin phenotype (26). Furthermore, keratinocyte-specific inducible STAT3 knockout can reduce psoriasis-like symptoms and afford greater protection against psoriasis-like dermatitis than that of constitutive deletion of STAT3 in all T cells (27). Herein, we found that STAT3 activation (STAT3 phosphorylation) was significantly reduced in IMQ-treated
Materials and methods are described in Supplementary Information.
This work was supported by the Science Research Center Program (Cellular Heterogeneity Research Center, NRF-RS-2023-00207857) to KIK, and by the Basic Science Research Program (2020R111A1A01068126) to KCP, through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT).
The authors have no conflicting interests.