BMB Reports 2023; 56(5): 296-301  https://doi.org/10.5483/BMBRep.2022-0169
Alleviation of imiquimod-induced psoriasis-like symptoms in Rorα-deficient mouse skin
Koog Chan Park1,2, Jiwon Kim2, Aram Lee1,2, Jong-Seok Lim1,2 & Keun Il Kim1,2,*
1Research Institute of Women’s Health, Sookmyung Women’s University, Seoul 04310, 2Department of Biological Sciences, Cellular Heterogeneity Research Center, Sookmyung Women’s University, Seoul 04310, Korea
Correspondence to: Tel: +82-2-710-9768; Fax: +82-2-2077-7322; E-mail: kikim@sookmyung.ac.kr
Received: October 24, 2022; Revised: November 15, 2022; Accepted: January 25, 2023; Published online: February 10, 2023.
© Korean Society for Biochemistry and Molecular Biology. All rights reserved.

cc This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
ABSTRACT
Retinoic acid receptor-related orphan receptor α (RORα) plays a vital role in various physiological processes, including metabolism, cancer, circadian rhythm, cerebellar development, and inflammation. Although RORα is expressed in the skin, its role in skin physiology remains poorly elucidated. Herein, Rorα was expressed in the basal and suprabasal layers of the epidermis; however, keratinocyte-specific Rorα deletion did not impact normal epidermal formation. Under pathophysiological conditions, Rorα-deficient mice exhibited alleviated psoriasis-like symptoms, including relatively intact epidermal stratification, reduced keratinocyte hyperproliferation, and low-level expression of inflammatory cytokines in keratinocytes. Unexpectedly, the splenic population of Th17 cells was significantly lower in keratinocyte-specific RORα deficient mice than in the control. Additionally, Rorα-deficiency reduced imiquimod-induced activation of nuclear factor-κB and STAT3 in keratinocytes. Therefore, we expect that RORα inhibitors act on immune cells and keratinocytes to suppress the onset and progression of psoriasis.
Keywords: Imiquimod, Keratinocytes, Psoriasis, RORα, STAT3
INTRODUCTION

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 Rora gene in keratinocytes. Notably, we found that a lack of RORα could alleviate psoriasis-like symptoms.

RESULTS

Keratinocyte-specific Rora deletion alleviates IMQ-induced psoriasis-like symptoms in mouse skin

As no systematic analysis regarding the contribution of RORα in skin physiology has been reported, we established a mouse model containing a keratinocyte-specific Rora deletion by crossing Rora-floxed mice with mice expressing Cre recombinase under the control of the keratin 14 promoter (K14-Cre) (Fig. 1A). The genotype of the mice was confirmed by PCR (Fig. 1B). We adapted the IMQ-induced psoriasis-like model to examine the role of RORα in pathophysiological conditions (10). IMQ-containing Aldara cream was applied daily to the dorsal surface and ear skin of mice for six days, and psoriasis-like symptoms were examined. The dorsal skin of Rora+/+ (hereafter, Rora+/+;K14-Cre) mice exhibited flaky erythema and psoriasis-like lesions six days after IMQ application, whereas RoraD/D (hereafter, Roraf/f;K14-Cre) mice indicated mild symptoms (Fig. 1C). On histological examination of dorsal and ear skin, IMQ-treated mice presented epidermal hyperplasia, resulting in skin thickening, keratosis, and elevated infiltration of the epidermal layer into the dermis in Rora+/+ mice, whereas RoraD/D mice indicated relatively well-defined epidermal layers (Fig. 1D, E). Measurement of epidermal thickness confirmed that the thickness of the epidermis was reduced (approximately 3-fold) in RoraD/D mice when compared with that of Rora+/+ mice (Fig. 1D). Topical IMQ application can reportedly induce splenomegaly in mice (10, 20). Accordingly, we compared the splenic size and mass before and after IMQ treatment in Rora+/+ and RoraD/D mice. Topical IMQ application increased the splenic size in both groups; however, the size was relatively smaller (closer to normal) in RoraD/D mice than in Rora+/+ mice (Fig. 1F). The mean splenic mass indicated a pattern similar to its size assessment (Fig. 1G). We then examined the population of Th17 cells in the spleen in comparison with Rora+/+ and RoraD/D mice before and after IMQ treatment. The spleen population of Th17 cells was increased approximately three-fold by IMQ treatment in Rora+/+ mice, whereas it was hardly increased in RoraD/D mice (Fig. 1H). These findings suggested that Rora deficiency could alleviate the IMQ-induced psoriasis-like symptoms in mice. Thus, Rora may contribute to the progression of psoriasis via its keratinocyte-mediated functions.

The epidermis of RoraD/D mice maintained a more intact stratification in the IMQ-induced psoriasis-like state

We performed immunostaining to detect Rora expression in the skin epidermis and found that the pattern of Rora immunostaining was in good agreement with that of K14, a marker of the basal epidermal layer involved in cell division (Fig. 2A). RoraD/D mice displayed normal overall skin appearance and epidermal stratification when compared with those of Rora+/+ mice (Fig. 2); this indicated that the lack of Rora expression does not impact the epidermal development. Interestingly, IMQ application increased Rora expression, as indicated by immunostaining (Fig. 2A) and immunoblotting (Fig. 2D) of primary mouse keratinocytes. HaCaT human keratinocytes exhibited increased RORα levels following IMQ treatment (Fig. 2E). Next, we investigated the status of epidermal stratification as a measure of skin integrity. Dorsal skin specimens of Rora+/+ and RoraD/D mice were subjected to immunofluorescence staining for various stratification marker proteins, such as K14 (basal layer and hair follicles), K10 (basal and suprabasal layer), and loricrin (late differentiation marker in the outermost epidermal layer) (10, 20). Herein, K14 and K10 were arranged in uniform and smooth layers in both Rora+/+ and RoraD/D mice without IMQ treatment (Fig. 2B). Upon IMQ treatment, the K14- and K10-expressing layers thickened and infiltrated into the dermal layer of the skin of Rora+/+ mice; however, the epidermis of RoraD/D mice presented a relatively normal structure approximating that of non-IMQ-treated mice (Fig. 2B). Loricrin staining revealed a disrupted structure of the outermost epidermal layer in IMQ-treated Rora+/+ mice when compared with the relatively normal layer of RoraD/D mice (Fig. 2C). Protein levels of late differentiation markers, including involucrin and loricrin, were similar before and after IMQ treatment in both mouse genotypes (Fig. 2D), indicating that the lack of differentiation markers fails to clarify abnormal stratification. In addition to aberrant stratification, alterations in tight junctions and downregulation of tight junction proteins in the epidermis have been documented in plaque-type psoriasis (21, 22). We analyzed the expression of occludin, a well-known tight junction protein in the epidermis. We noted that occludin expression was reduced in the skin of IMQ-treated Rora+/+ mice when compared with that in the untreated control, as determined by immunofluorescence and immunoblotting analyses (Fig. 2F, G). Convertsely, IMQ-treated RoraD/D mice maintained occludin expression along the epidermal layer (Fig. 2F, G). Another tight junction protein, claudin, indicated a pattern resembling that of occludin in the immunoblotting analysis (Fig. 2G). Collectively, these results suggested that Rora deficiency can favorably maintain the epidermal structure of the skin during IMQ-induced psoriasis-like conditions.

Rora-deficient keratinocytes exhibited reduced hyperproliferation in IMQ-induced psoriasis-like conditions

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 Rora+/+ and RoraD/D mice. IMQ increased the number of Ki67-positive cells more than two-fold in the epidermis of Rora+/+ mice, with only a slight increase noted in RoraD/D mice (Fig. 3A, B). To confirm these findings, we knocked out RORa in HaCaT cells and examined cell division before and after IMQ treatment. After validating the effective knockout of RORa (Fig. 3C), we measured EdU incorporation into newly synthesized DNA as an indicator of cell proliferation. IMQ treatment significantly increased the number of EdU-incorporated HaCaT cells, indicating cellular hyperproliferation. Conversely, RORa-deficient cells exhibited a slight increase in EdU incorporation following IMQ treatment (Fig. 3D). Statistical analysis revealed that control HaCaT cells indicated a nearly three-fold increase in EdU-positive cells upon IMQ treatment; however, only a slight increase was documented in RORa-deficient cells (Fig. 3E). Collectively, these results suggested that RORa deficiency in keratinocytes could suppress their hyperproliferation in IMQ-induced psoriasis-like conditions.

Reduced proinflammatory gene expression and attenuated nuclear factor (NF)-κB and signal transducer and activator of transcription 3 (STAT3) activation in Rora-deficient keratinocytes upon IMQ treatment

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 Rora+/+ and RoraD/D mice, treated isolated cells with IMQ, and subsequently obtained cell lysates. The production of cytokines, including tumor necrosis factor (TNF)-α, IL-6, IL-23, and chemokine (C-C motif) ligand 20 (CCL20), was evaluated using the Luminex kit (Multiplex chemokine and cytokine assay kit). The amounts of cytokines were relatively low in Rora-deficient keratinocytes when compared with that of wild-type controls, although fold increases in TNFα and IL-6 by IMQ treatment were similar in each group (Fig. 4A). In a similar set of experiments, IMQ treatment increased the phosphorylation of p65, an NF-κB subunit, in wild-type keratinocytes; only marginal phosphorylation was detected in keratinocytes derived from RoraD/D mice (Fig. 4B). Furthermore, IMQ-induced STAT3 phosphorylation was reduced in Rora-deficient keratinocytes when compared with that in wild-type keratinocytes (Fig. 4C). To confirm whether RORa deficiency reduces the activation of proinflammatory signaling, we performed transient knockout of the RORa gene in HaCaT cells. As observed in Rora-deficient primary keratinocytes, we confirmed that IMQ-induced activation of NF-κB and STAT3 was reduced in RORa-KO HaCaT cells (Fig. 4D, E). We then examined the interaction between endogenous RORα and STA3 in keratinocyte cells. When extracts of HaCaT cells were immunoprecipitated with an anti-STAT3 antibody, we detected endogenous RORα in the precipitate, and the amount of RORα detected increased upon IMQ treatment (Fig. 4F). Transient RORα knockout diminished this interaction (Fig. 4F). Moreover, IMQ-induced upregulation of proinflammatory gene expression was blunted in RORa-knockout HaCaT cells (Fig. 4G). Overall, these results indicated that RORa deficiency has a causal relationship with a reduced inflammatory status in IMQ-treated keratinocytes. The reduced inflammation may be responsible for alleviating IMQ-induced psoriasis-like conditions in RoraD/D mice.

DISCUSSION

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 Rora-deficient keratinocytes, including K10, loricrin, involucrin, and filaggrin. However, despite the low expression of these keratinocyte genes, we did not find any structural problems in the epidermal layer of RoraD/D mice. Thus, in the present study, we focused on the role of RORα in keratinocytes during the development and progression of psoriasis. K14-Cre removes floxed exons in the Rora gene of epidermal keratinocytes but not immune cells; hence, we expected to exclude the contribution of RORα in psoriasis progression through its function in immune cells, including Th17 cells. However, keratinocyte-specific deletion of Rora still significantly reduced the splenic population of Th17 cells upon IMQ treatment. Although we do not know the exact mechanism of how keratinocyte-specific deletion of the Rora gene decrease the development of Th17 cells, we think that this is one reason of alleviated psoriasis-like symptoms in Rora-deficient mouse skin. In addition to the reduced Th17 cells, we found that RORα deficiency reduced cell proliferation and decreased proinflammatory cytokine gene expression, two well-known aspects of psoriasis progression, in both primary mouse keratinocytes and human HaCaT cells. Accordingly, it can be suggested that RORα plays an important role in keratinocyte hyperproliferation and inflammatory processes in an IMQ-induced psoriasis model, and inhibition of RORα may be valuable for attenuating the progression of psoriasis.

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 RORa-deficient keratinocytes. Reportedly, RORα directly interacts with STAT3, and treatment with a RORα antagonist or knockdown of RORα inhibits STAT3 activation in human articular chondrocytes, although the examined cell type varies from that used in the present study (28). We also confirmed the interaction between RORα and STAT3 in keratinocytes, and STAT3 phosphorylation was reduced in the absence of RORα in both mouse primary keratinocytes and HaCaT cells. Therefore, inhibition of RORα appears to be effective in both immune cells and keratinocytes to suppress the development and progression of psoriasis, and inverse RORα agonists may represent a new class of anti-inflammatory compounds to treat inflammatory skin diseases, including psoriasis.

MATERIALS AND METHODS

Materials and methods are described in Supplementary Information.

ACKNOWLEDGEMENTS

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).

CONFLICTS OF INTEREST

The authors have no conflicting interests.

FIGURES
Fig. 1. Evaluation of IMQ-induced psoriasis-like symptoms in skin-specific Rorα-deficient mice. (A) Rorα floxed mice were crossed with K14-Cre mice leading to keratinocyte-specific deletion of exons 4 and 5 in the Rorα gene. (B) Genotyping results for the skin-specific deletion of Rorα confirm the successful deletion of exons 4 and 5 in the Rorα gene. (C) Rorα+/+ and RorαD/D mice were topically treated with 62.5 mg of Aldara cream (containing 5% IMQ), applied daily on the shaved dorsal skin surface for six days. (D) Representative images of hematoxylin and eosin (H&E) staining of paraffin sections of the dorsal skin of each group of mice, prepared as indicated in (C) (left panel). Scale bar; 100 μm. The mean thickness of the epidermis of each group of mice was measured using H&E stained images (right panel, n = 6). Data are presented as mean ± standard error of the mean (SEM). ***P < 0.001. (E) Representative images of H&E staining of the ear skin. (F) Representative images of the spleen from each group of mice, prepared as indicated in (C). (G) The spleen mass was calculated from six independent mice for each group. Data are presented as mean ± SEM. *P < 0.05. (H) The splenic population of Th17 cells was calculated from four independent mice for each group. Data are presented as mean ± SEM. *P < 0.05. IMQ, imiquimod; RORα, Retinoic acid receptor-related orphan receptor α.
Fig. 2. Analysis of epidermal stratification and barrier formation of the skin. (A-C) Skin sections were subjected to immunofluorescence analyses with antibodies against (A) Keratin 14 (K14, green) and Rorα (red), (B) K14 (green) and K10 (red), and (C) K14 (green) and loricrin (red). Scale bar = 100 μm. (D, E) Immunoblot analysis for various stratification marker proteins. Mouse primary keratinocytes (D) or HaCaT cells (E) were treated with IMQ for 24 h, and protein extracts were subjected to immunoblotting for indicated proteins. The equal protein loading was confirmed with GAPDH. (F) Skin sections were subjected to immunofluorescence analyses with antibodies against occludin, a tight junction protein. Scale bar = 100 μm. (G) The expression of occludin and claudin was analyzed as in (D). IMQ, imiquimod.
Fig. 3. Assessment of IMQ-induced proliferation of wild-type and RORα-deficient human and mouse keratinocytes. (A) Skin sections were subjected to immunofluorescence analysis with an antibody against Ki67 (red), a cell proliferation marker. Scale bar = 100 μm. (B) The number of Ki67-positive keratinocyte cells was counted in four images from each independent mouse skin, expressed as a percentage of total cells. Data are shown as mean ± standard error of the mean (SEM). **P < 0.01. (C) HaCaT cells were infected with lentivirus generated from the pLentiCRISPR-E vector or pLentiCRISPR-E-RORα #1 in six-well plates. One day after viral infection, cells were selected with 1 μg/ml puromycin for 2 days. Pools of selected HaCaT cells were treated with 200 μM IMQ for 24 h and subjected to immunoblot analysis for RORα. Control represents HaCaT cells infected with lentivirus generated from the pLentiCRISPR-E vector, and RORα knockout (KO) represents the case of pLentiCRISPR-E-RORα #1. (D) HaCaT cells prepared as in (C) were seeded in 12-well plates at a density of 1 × 105 cells per well, treated with IMQ for 24 h, and then EdU labeled for 24 h. EdU-positive cells indicate a red color. Scale bar = 100 μm. (E) The number of EdU-positive cells was counted in four images from each independent experiment, expressed as a percentage of total cells. Data are shown as mean ± SEM. ***P < 0.001. IMQ, imiquimod; RORα, Retinoic acid receptor-related orphan receptor α.
Fig. 4. Reduced activation of IMQ-induced inflammatory signals in RORα-deficient keratinocyte cells. (A) Primary keratinocytes from the skin of newborn Rorα+/+ and RorαD/D mice were treated with 200 μM IMQ for 24 h, and cytokine levels were determined using Luminex-based multiplex assay from keratinocyte cell lysates (n = 3, three mice for each group). Data are presented as mean ± standard error of the mean (SEM). *P < 0.05; **P < 0.01, ns; not significant. (B, C) Primary keratinocytes prepared as in (A) were subjected to immunoblot analyses to evaluate the activation (phosphorylation) of NF-κB (B) and STAT3 (C). Equal protein loading was confirmed with GAPDH. (D, E) Knockout of the RORα gene was performed as described in Fig. 3C. HaCaT cells were treated with 200 μM IMQ for 24 h and subjected to immunoblot analyses to evaluate the activation (phosphorylation) of NF-κB (D) and STAT3 (E). (F) Extracts of HaCaT cells were immunoprecipitated with anti-STAT3 antibody and then blotted with antibodies indicated. (G) Control and RORα knockout HaCaT cells were treated with 200 μM IMQ for 24 h, and the expression of cytokine genes was evaluated by real-time PCR analysis. Data are presented as mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001. IMQ, imiquimod; NF κB, nuclear factor-κB; RORα, Retinoic acid receptor-related orphan receptor α; STAT3, signal transducer and activator of transcription 3.
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Funding Information
  • National Research Foundation of Korea
      10.13039/501100003725
      NRF-RS-2023-00207857, 2020R111A1A01068126
  • Ministry of Science and ICT, South Korea
      10.13039/501100014188
      NRF-RS-2023-00207857, 2020R111A1A01068126

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