Imiquimod-induced Psoriasis Research Articles

Inducible nitric oxide synthase-expressing myeloid-derived suppressor cells regulated by interleukin 35 contribute to the pathogenesis of psoriasis.

Although psoriasis is classified as a T cell-mediated inflammatory disease, the contribution of myeloid cells to the pathogenesis of psoriasis is not fully understood. In the present study, we demonstrated that the expression of the anti-inflammatory cytokine interleukin-35 (IL-35) was significantly increased in patients with psoriasis with a marked increase in the number of myeloid-derived suppressor cells (MDSCs). Similar results were obtained in an imiquimod-induced psoriasis mouse model. IL-35 reduced the total number of MDSCs and their subtypes in the spleens and psoriatic skin lesions, ameliorating psoriasis. IL-35 also reduced the expression of inducible nitric oxide synthase in MDSCs, although it had no significant effect on interleukin-10 expression. Adoptive transfer of MDSCs from imiquimod-challenged mice aggravated the disease and weakened the effect of IL-35 in the recipient mice. In addition, mice transferred with MDSCs isolated from inducible nitric oxide synthase knockout mice had milder disease than those with wild-type MDSCs. Furthermore, wild-type MDSCs reversed the effects of IL-35, while MDSCs isolated from inducible nitric oxide synthase knockout mice did not affect IL-35 treatment. In summary, IL-35 may play a critical role in the regulation of iNOS-expressing MDSCs in the pathogenesis of psoriasis, highlighting IL-35 as a novel therapeutic strategy for patients with chronic psoriasis or other cutaneous inflammatory diseases.

Banzhilian formula alleviates psoriasis-like lesions via the LCN2/MMP-9 axis based on transcriptome analysis.

Introduction: Oral Banzhilian formula (BZLF) is effective in the clinical treatment of psoriasis. However, the effectiveness and mechanism of different drug delivery routes deserve further study. Methods: First, we established the mouse model of psoriasis using imiquimod (IMQ), and high-performance liquid chromatography (HPLC) was used for the quality control of BZLF. Secondly, Total RNA Sequencing and bioinformatics analysis were used to explore the regulatory mechanism of BZLF in improving psoriatic lesions. Finally, further verification was based on animal experiments. Results: we externally applied BZLF for skin lesions in an imiquimod-induced psoriasis mouse model and found that BZLF alleviated psoriasis-like skin lesions while inhibiting the expression of Ki67 and inflammatory factors (Il17a, Tnf-α, S100a7 and Cxcl1) in skin lesions. Transcriptome sequencing results suggested that BZLF inhibited signalling pathways closely related to psoriatic inflammation, such as the IL-17 signalling pathway, chemokine signalling pathway, TNF signalling pathway, and NF-kappa B signalling pathway, and the protein-protein interaction (PPI) network identified LCN2 as one of the core target genes and screened out its regulated downstream gene MMP9. Discussion: Our findings suggest that the anti-psoriatic mechanism of BZLF involved in downregulating the LCN2/MMP-9 axis.

Discovery of orally bioavailable inhibitors of MALT1 with in vivo activity for psoriasis

We report the design, synthesis, and biological activity of a series of compounds that exhibit potent mucosa-associated lymphoid tissue lymphoma translocation 1 (MALT1) inhibition. Structural transformation of the substructures of a starting compound gave amidomethyl derivatives and sulfonylguanidine derivatives that exhibited potent inhibition of MALT1. Compound 37 had good oral bioavailability and showed anti-psoriatic activity in an imiquimod-induced psoriasis mouse model after oral administration.

An integrated Mg battery-powered iontophoresis patch for efficient and controllable transdermal drug delivery

Wearable transdermal iontophoresis eliminating the need for external power sources offers advantages for patient-comfort when deploying epidermal diseases treatments. However, current self-powered iontophoresis based on energy harvesters is limited to support efficient therapeutic administration over the long-term operation, owing to the low and inconsistent energy supply. Here we propose a simplified wearable iontophoresis patch with a built-in Mg battery for efficient and controllable transdermal delivery. This system decreases the system complexity and form factors by using viologen-based hydrogels as an integrated drug reservoir and cathode material, eliminating the conventional interface impedance between the electrode and drug reservoir. The redox-active polyelectrolyte hydrogel offers a high energy density of 3.57 mWh cm−2, and an optimal bioelectronic interface with ultra-soft nature and low tissue-interface impedance. The delivery dosage can be readily manipulated by tuning the viologen hydrogel and the iontophoresis stimulation mode. This iontophoresis patch demonstrates an effective treatment of an imiquimod-induced psoriasis mouse. Considering the advantages of being a reliable and efficient energy supply, simplified configuration, and optimal electrical skin-device interface, this battery-powered iontophoresis may provide a new non-invasive treatment for chronic epidermal diseases.

Comparative studies on mannan and imiquimod induced experimental plaque psoriasis inflammation in inbred mice.

Psoriasis is a genetically determined, environmentally triggered, immune system-mediated autoimmune disease. Different animal models are needed to investigate the complex pathological mechanisms underlying this disease. Therefore, we established mannan-induced psoriasis model and compared with the most commonly used imiquimod-induced psoriasis in terms of disease, induction of innate immune cells, expression of cytokines, and the effect of dexamethasone treatment. Mannan significantly induced more severe psoriasis with better disease relapsing feature than imiquimod (IMQ). As determined by immunohistochemistry, IMQ induced significantly more infiltration of CD11c+ and F4/80+ cells than mannan in the skin. However, cytometric analysis showed a significant increase in the percentage of Gr-1+ neutrophils in the spleen and lymph nodes as well as F4/80+ macrophages in the spleen after mannan exposure. Variation in the percentage of significantly increased Vγ4 T cells was also found to be dependent on the lymphoid organs tested. However, there is a clear difference between these models in terms of expression of certain cytokine genes: IL-22, IL-23, IL-17E, and IL-17F were expressed more predominantly in mannan-induced inflammation, while IL-6 and IL-17A expressions were significantly higher in IMQ model. Interestingly, dexamethasone treatment strongly reduced epidermal thickness and histological scores induced by mannan than IMQ. Despite inducing psoriasis-like inflammation, certain differences and similarities were observed in the immune responses induced by mannan and IMQ. However, mannan-induced psoriasis model is relatively more simple, economical and less harmful to mice with an increased possibility to develop a chronic psoriasis model by exposing mice to mannan.

Effect of Lenalidomide Ointment on TNF-α Tissue Levels in Mice with Imiquimod-Induced Psoriasis.

Background: Lenalidomide is an immunomodulatory drug having notable anti-inflammatory, and anti-antineoplastic properties. Lenalidomide suppresses the production of pro-inflammatory cytokines that have been linked to a variety of hematologic malignancies. Lenalidomide enhances the immune system of the host by regulating T cell proliferation, which results in changes in inflammation that are related to the etiology of psoriasis. Objectives: The objectives of this study were to determine the efficacy of lenalidomide as an ointment in treating mouse models of psoriasis as well as how it may affect TNF-α levels in skin tissue in different experimental groups. Methods: The study was carried out between November 2021 and June 2022. 70 healthy male albino mice were randomly divided into 7 groups of 10 animals each. In groups (1, 2, 3, 4, 5 and 6), imiquimod produced psoriasis. Only imiquimod cream was administered to Group 1, after psoriasis induced, Clobetasol ointment was applied to Group 2, placebo ointment was applied to Group 3, and lenalidomide ointment (1%, 2%, and 3%) were applied to Groups (4, 5, and 6), respectively. Healthy mice were utilized as a comparative control in Group 7. SPSS was utilized for the statistical analysis of the data (version 26). Results: Following lenalidomide treatment, the psoriatic region improved. Lenalidomide's effectiveness to treat imiquimod-induced mouse psoriasis was explained by the difference in tissue levels of TNF-α between the examined groups. Conclusions: Findings suggest that different concentrations of lenalidomide ointment can improve mouse models of imiquimod-induced psoriasis. Histopathology and immunohistochemistry assays show that lenalidomide ointment was more effective and had no side effects that were associated with the use of the standard drugs.

Development and evaluation emulgel for effective management of the imiquimod-induced psoriasis.

Our main aim is in the present investigation, development and evaluation of seabuckthorn oil-based Emulgel formulation for psoriasis therapy. Anti-psoriatic activity of the SeaEmulgel was studied using Imiquimod-induced psoriasis-like inflammation model Balb/c mice and parameters such as PASI score, ear thickness, spleen to body weight index including histological staining studies, enzyme-linked immune sorbent assay (ELISA), skin compliance and safety evaluation of sea buckthorn oil was performed. The globule size and PDI of sea buckthorn oil emulsion were found to be 172.70 ± 1.73nm and 0.117 ± 0.018, respectively. In-vivo animal studies performed on male Balb/c mice and emulgel showed a reduction in redness, scaling, inflammation in psoriasis-induced mice, which was analysed by PASI scoring, body weight, spleen weight index and ear thickness. The current investigation clearly revealed the better anti-psoriatic activity of SeaEmulgel formulation against imiquimod-induced psoriasis-like skin inflammation Balb/c mice model.

Inhibition of Serum- and Glucocorticoid-Regulated Protein Kinase-1 Aggravates Imiquimod-Induced Psoriatic Dermatitis and Enhances Proinflammatory Cytokine Expression through the NF-kB Pathway

Although the anti-inflammatory effect of serum- and glucocorticoid-regulated protein kinase 1 (SGK1) has been established in other diseases, the possible regulatory role of SGK1 in psoriasis and the underlying molecular mechanisms remain largely unknown. In this study, we found that SGK1 expression was decreased in macrophages from patients with psoriasis. Moreover, a specific pharmacological SGK1 inhibitor, EMD638683, significantly enhanced imiquimod-mediated toll-like receptor 7/8 activity and proinflammatory cytokine production in RAW264.7 cells, and this result was confirmed by Sgk1 small interfering RNA. Further mechanistic data showed that SGK1 inhibition increased the phosphorylation of Bruton's agammaglobulinemia tyrosine kinase; moreover, Bruton's agammaglobulinemia tyrosine kinase inhibition abrogated the proinflammatory effects of the SGK1 inhibitor on toll-like receptor 7/8 activation, thereby validating that SGK1 inhibition enhances the toll-like receptor 7/8 pathway by increasing Bruton's agammaglobulinemia tyrosine kinase phosphorylation. In addition, our invivo results showed that SGK1 inhibition significantly increased the secretion of proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, and the infiltration of T helper 17 cells in an imiquimod-induced psoriasis mouse model. Altogether, these results show that SGK1 plays a critical role in the pathogenesis of psoriasis by modulating inflammatory responses in skin lesions, indicating that SGK1‒Bruton's agammaglobulinemia tyrosine kinase signaling could be a novel therapeutic target for the control of psoriasis.

Evaluation of Anti-Inflammatory Effect of Green Synthesized Gold Nanoparticles on Imiquimod Induced Psoriasis in Mice as Model

Evaluation of Anti-Inflammatory Effect of Green Synthesized Gold Nanoparticles on Imiquimod Induced Psoriasis in Mice as Model

Potential skin health promoting benefits of costunolide: a therapeutic strategy to improve skin inflammation in imiquimod-induced psoriasis.

Psoriasis is a recurrent inflammatory skin disease. IL-36-related cytokines are overexpressed in psoriasis, but the mechanism is not yet clear. Costunolide (Cos) is a sesquiterpenoid compound derived from the root of the traditional Chinese medicine Aucklandia lappa Decne. This study aimed to explore the mechanism of Cos on improving psoriasis-like skin inflammation. An in vivo model was established by applying imiquimod treatment to the back skin of mice, and an in vitro model was established by using polyinosinic-polycytidylic acid (Poly(I:C)) stimulated-mouse primary dermal fibroblasts to induce inflammation. The results showed that Cos improved the pathological changes of psoriasis-like skin inflammation. In addition, Cos could inhibit epidermal damage and inflammation-related expression and improve the occurrence of skin-related inflammation in both in vivo and in vitro experiments. The improvement of psoriasis-like skin inflammatory response might be through the P2X7R/IL-36 signaling pathway. Collectively, Cos has an inhibitory effect on the expression of psoriasis-like skin inflammation. This showed that Cos has potential skin health promoting benefits by preventing psoriasis-like skin inflammation.

Kaempferol modulates IFN-γ induced JAK-STAT signaling pathway and ameliorates imiquimod-induced psoriasis-like skin lesions

Immune-mediated inflammation contributes to the development of psoriasis. However, long-term treatment with global immunosuppressive agents may cause a variety of side effects including recurrent infections. Kaempferol (KP), a natural flavonol, present in various plants is proposed to be useful for the treatment of psoriasis patients. Nevertheless, an explicit understanding of KP induced mechanisms is a prerequisite for its use in clinics. Therefore, we investigated the therapeutic effects and potential mode of action of KP using IFN-γ induced HaCaT cells and imiquimod-induced psoriasis-like skin lesions in mice. In this study, we found KP reduced intracellular ROS production, inhibited rhIFN-γ-induced IFN-γR1 expression, and up-regulated SOCS1 levels in HaCaT cells. In addition, KP inhibited rhIFN-γ-induced phosphorylation of JAK-STAT signaling molecules in HaCaT cells. Most importantly, KP alleviated imiquimod-induced psoriasis-like skin lesions in mice, histopathology and proportion of DCs in the skin. Besides, it reduced the population of γδT17 cells in the lymph nodes of the psoriatic mice and also decreased the gene expression of many proinflammatory cytokines, including interleukin IL-23, IL-17A, TNF-α, IL-6, and IL-1β in addition to down-regulation of the proinflammatory JAK-STAT signaling pathway. Thus, KP modulated IFN-γ induced JAK-STAT signaling pathway by inducing IFN-γR1 expression and up-regulating SOCS1 expression. In addition, KP also ameliorated imiquimod-induced psoriasis by reducing the dendritic cell numbers, and γδT17 cell population, along with down- modulation of the JAK-STAT pathway.

Evaluation of the Involvement of Coiled-coil α-helical Rod Protein 1 (CCHCR1) in Imiquimod-induced Psoriasis Models.

Evaluation of the Involvement of Coiled-coil α-helical Rod Protein 1 (CCHCR1) in Imiquimod-induced Psoriasis Models.

Role of microsomal prostaglandin E synthase-1 in skin inflammation and T-cell immune response of imiquimod-induced psoriasis in mice.

Role of microsomal prostaglandin E synthase-1 in skin inflammation and T-cell immune response of imiquimod-induced psoriasis in mice.

Trichinella pseudospiralis-secreted 53 kDa protein ameliorates imiquimod-induced psoriasis by inhibiting the IL-23/IL-17 axis in mice

Trichinella infection can experimentally ameliorate many autoimmune diseases. However, the immune mechanism of the amelioration and the identification of corresponding Trichinella-derived molecule(s) are still not fully elucidated. Fifty-three kDa excretory-secretory (ES) protein from Trichinella pseudospiralis (Tpp53) is a molecule like TsP53 reported as a protein exerting immune-inhibitory effect in T. spiralis. In this study, we investigated the immunomodulatory effect of Tpp53 using imiquimod (IMQ)-induced psoriasis-like dermatitis model, which is a mouse model of autoimmune disease with the pathogenic interleukin 17 (IL-17) producing CD4+ T cells (Th17) via IL-23/IL17 axis. Administrating the recombinant Tpp53 (rTpp53) mixed with IMQ cream on the skin of mice ameliorated psoriatic lesions, as revealed by the improvement of erythema, scaling, skin thickening, epidermis hyperplasia and parakeratosis, thickening of acanthosis cell layer, epidermal extension of dermis, less infiltration of inflammatory cells, and decreased expression of inflammatory marker. The increased expression of the factors related to the IL-23/IL-17 axis, including IL-17A, IL-6, Il17F and Il23a, in the skins of IMQ-treated mice was inhibited by rTpp53 treatment. Moreover, the expression of activated keratinocyte-produced cytokines, chemokines, and antimicrobial peptides in the skin was also down-regulated in rTpp53-treated IMQ-treated mice. Co-culture of splenocytes with rTpp53 inhibited IL-17A and treatment of macrophages with rTpp53 reduced IL-6 production. Overall, our study revealed that the Trichinella-secreted 53 kDa ES protein could ameliorate IMQ-induced psoriasis by inhibiting the IL-23/IL-17 axis, suggesting that Tpp53 might involve in regulating host Th17 for immune evasion and have an alternative potential for psoriasis therapy.

Lipidomic profiling reveals metabolic signatures in psoriatic skin lesions

Psoriasis is a chronic immune-mediated inflammatory disease. Lipids play an important role in regulating the inflammatory response. However, the alteration of lipids involved in psoriasis particular in skin lesions remain unclear. Here, we performed the lipidomics to investigate lipid profiling in the skin lesions of the imiquimod-induced psoriasis-like dermatitis and psoriasis patients. The findings showed that ceramides phosphate (CerP) and ceramides were enriched in psoriatic lesions compared with controls from both psoriasis patients and psoriasis-like mouse model. Psoriasis patients were classified into two subtypes, the CC1 and CC2, by consensus clustering of these lipid signatures. The CC1 was characterized by the higher levels of CerP, uric acid, and more severe psoriasis, compared with CC2 subtype. Interestingly, ceramide-1-phosphate (C1P), dramatically enriched in CC1 subtype, facilitated imiquimod-induced psoriasis-like inflammatory responses. Mechanistically, C1P induced the expression of inflammatory factors and activated DNA replication and cell cycle signaling pathways in the primary keratinocytes. Inhibiting the production of C1P with ceramide kinase inhibitor effectively alleviated the imiquimod-induced psoriasis-like inflammation. Taken together, we described the landscape of lipids alteration and established lipids classification based on pattern of abundance of lipids in psoriatic skin lesions. Suppression of C1P pathway is a novel potential strategy for psoriasis treatment.

Targeting TGF-β1/miR-21 Pathway in Keratinocytes Reveals Protective Effects of Silymarin on Imiquimod-Induced Psoriasis Mouse Model

Epidermal cells integrate multiple signals that activate the signaling pathways involved in skin homeostasis. TGF-β1 signaling pathway upregulates microRNA (miR)-21-5p in keratinocytes and is often deregulated in skin diseases. To identify the bioactive compounds that enable to modulate the TGF-β1/miR-21-5p signaling pathway, we screened a library of medicinal plant extracts using our miR-ON RILES luciferase reporter system placed under the control of the miR-21-5p in keratinocytes treated with TGF-β1. We identified silymarin, a mixture of flavonolignans extracted from Silybum marianum (L.) Gaertn., as the most potent regulator of miR-21-5p expression. Using Argonaute 2 immunoprecipitation and RT-qPCR, we showed that silymarin regulates the expression of miR-21-5p through a noncanonical TGF-β1 signaling pathway, whereas RNA-sequencing analysis revealed three unexpected transcriptomic signatures associated with keratinocyte differentiation, cell cycle, and lipid metabolism. Mechanistically, we demonstrated that SM blocks cell cycle progression, inhibits keratinocyte differentiation through repression of Notch3 expression, stimulates lipid synthesis via activation of PPARγ signaling and inhibits inflammatory responses by suppressing the transcriptional activity of NF-κB. We finally showed that topical application of silymarin alleviates the development of imiquimod-induced psoriasiform lesions in mice by abrogating the altered expression levels of markers involved in inflammation, proliferation, differentiation, and lipid metabolism.

341 Imiquimod-induced psoriasis requires non-classical monocytes

Psoriasis is a chronic inflammatory skin disease caused by an IL-23- and IL-17 driven immune response. Monocytes are regarded as key immune regulatory cells, which can be divided into three well-defined subsets: classical monocytes, intermediate monocytes, and non-classical monocytes (ncMo). The function of ncMo in skin inflammation remains largely unknown. Yet, our previous studies on slan+ (6-sulfo LacNAc) ncMo suggested that these cells contribute to human psoriasis skin inflammation. We here report on the role of ncMo in a model of psoriasis-like skin inflammation induced by imiquimod (IMQ).

376 Activation of linear ubiquitination by linear ubiquitin chain assembly complex specifically exacerbates a murine imiquimod-induced psoriasis model

Nuclear factor-κB (NF-κB) is important in inflammatory skin diseases, including contact dermatitis (Th1 inflammation), atopic dermatitis (Th2 inflammation), and psoriasis (Th17 inflammation). In fact, molecularly targeted drugs against tumor necrosis factor (TNF), which is both upstream and downstream of NF-κB have been demonstrated to be effective in skin diseases such as psoriasis. The linear ubiquitination by linear ubiquitin chain assembly complex (LUBAC), which consists of HOIL-1L, HOIP and SHARPIN, is activating IKKβ, which is essential for TNF/NF-κB signaling.

Tryptanthrin ameliorates imiquimod-induced psoriasis in mice by suppressing inflammation and oxidative stress via NF-κB/MAPK/Nrf2 pathways.

Nowadays, approximately 3% of the world's population suffers from psoriasis, an inflammatory dermatosis with high recurrence. Tryptanthrin (TRYP) is a natural alkaloid that possesses anti-inflammatory activities on multiple diseases. The present study aimed to unravel whether TRYP could relieve psoriasis and how it works. Imiquimod (IMQ)-induced psoriatic mouse models were administered saline (model), TRYP (25 and 100mg/kg), or methotrexate (MTX, 1mg/kg) and considered as the positive control. TNF-α-induced keratinocytes (HaCaT cells) with TRYP (0, 10, 20 and 50nM) were used for in vitro verification. Psoriasis area severity index (PASI) and spleen index were evaluated. Th17 cell infiltration in both spleens and lymph nodes was detected by flow cytometry. The expression levels of inflammatory cytokines, glutathione (GSH), malondialdehyde (MDA) and catalase (CAT), as well as superoxide dismutase (SOD), were examined by ELISA, while the NF-κB/MAPK/Nrf2 pathways-related proteins were determined by western blot. TRYP significantly attenuated psoriatic skin lesions, increased GSH, SOD, and CAT levels, reduced spleen index, accumulation of MDA, the abundance of Th17 cells in both the spleen and lymph nodes, and secretion of inflammatory cytokines in IMQ-induced psoriatic mouse models. Mechanically, TRYP suppressed IMQ-activated NF-κB (IκB and p65), MAPK (JNK, ERK1/2, and p38), and activated Nrf2 signaling pathways. Similar alterations for inflammation and oxidative stress parameters and NF-κB/MAPK/Nrf2 pathways were also observed in TNF-α-treated HaCaT cells upon TRYP treatment. Our findings suggested TRYP is effective in protecting against inflammation and oxidative stress in psoriasis-like pathogenesis by modulating the NF-κB/MAPK/Nrf2 pathways.

Interleukin 17 Receptor C, but not Polo-like Kinase 4, Plays a Critical Role in the Development of Skin Papilloma and Psoriasis in Mouse Models

Abstract Introduction/Objective Hyperproliferation of epidermis is a histopathological hallmark of skin cancers and psoriasis. As a master regulator of centriole replication, overexpression of Polo-like kinase 4 (PLK4) has been identified in skin cancers. The aberrant proliferation of epidermal keratinocytes provoked by interleukin 17 (IL17) leads to psoriasis. Thus, targeting centriole replication and IL17 signaling simultaneously has been speculated as a potential therapeutic strategy. We hypothesized that inhibition of centriole duplication enhances the blockade of epidermal proliferation through Il17rc knockout. Methods/Case Report To test our hypothesis, 37 mice were used to imbed a two-stage model of skin carcinogenesis using wild-type (WT), IL17 receptor A (T779A) knock-in (Il17ra(T779A)-KI), and IL17 receptor C knock-out (Il17rc-KO) C57BL/6J mouse strains. Furthermore, an imiquimod-induced psoriasis model was established using 69 mice with the same strains. Results (if a Case Study enter NA) In our two-stage skin carcinogenesis model, Il17ra(T779A)-KI mice showed significantly decreased tumor incidence, tumor multiplicity, and tumor volume compared to the WT mice. Il-17rc-KO mice didn’t develop any skin papilloma. The skin papilloma formed never progressed into squamous carcinoma. However, centrinone, a selective inhibitor of PLK4, didn’t affect skin papilloma formation or epidermal thickening. In our psoriasis model, the epidermis thickness of Il-17rc-KO mice was dramatically decreased compared to WT and Il17ra(T779A)-KI mice. There was no significant difference between WT and Il17ra(T779A)-KI mice in terms of skin lesion and thickening of the epidermis. Centrinone didn’t stall the thickening of the epidermis in the psoriasis model. IHC staining showed significantly increased Ki67+ basal keratinocytes in the untreated skin of Il17ra(T779A)-KI male mice compared to WT mice. In imiquimod-treated skin, the percentage of Ki67+ basal keratinocytes significantly decreased in the order from WT, Il17ra(T779A)-KI to Il17rc-KO mice. Conclusion Our data suggest that the proliferation of keratinocytes is not stalled by centrinone but is inhibited by Il17rc-KO. Il17ra(T779A)-KI significantly inhibits skin papilloma formation, but slightly decreases epidermal thickening in the psoriasis model. However, Il17ra(T779A)-KI increases keratinocyte proliferation based on Ki67 staining in the untreated normal skin.