Development of Imiquimod-induced HaCaT-THP-1 co-culture for modeling of psoriasis.

Psoriasis is one of the most prevalent and chronic inflammatory disease of the skin, associated with disrupted barrier function. Currently, a widely accepted, generally usable cell culture model has not been developed yet. In the present work, we aimed to establish a co-culture model with human keratinocyte (HaCaT) and human monocyte cells (THP-1) induced by Imiquimod (IMQ), which acts on the TLR7 receptor. The role of TLR7 expressed on THP-1 cells was confirmed by immunofluorescence staining of NF-κB activation. Chloroquine (CH) was used as a receptor inhibitor, in the presence or absence of which the NF-κB pathway was activated. We determined the most effective proliferation-stimulating IMQ concentration by RTCA method and the hyperproliferative effect was investigated by wound-healing test. The effect of IMQ was compared with the effects of the anthocyanin (AC) components from the anti-inflammatory sour cherry extract that we have already studied. We found that IMQ significantly increased the migration rate however, the combined treatment resulted in a decreased migration rate compared to the IMQ treatment alone. Inflammatory cytokines were measured from the supernatant of co-culture by ELISA. During the development of the co-culture intended to model psoriasis, we confirmed the induction effect of IMQ and in the case of AC treatment, we supported the stabilizing effect of the barrier.

Phenotypical and biochemical characterization of murine psoriasiform and fibrotic skin disease models in Stabilin-deficient mice.

Stabilin-1 (Stab1) and Stabilin-2 (Stab2) are scavenger receptors expressed by liver sinusoidal endothelial cells (LSECs). The Stabilin-mediated scavenging function is responsible for regulating the molecular composition of circulating blood in mammals. Stab1 and Stab2 have been shown to influence fibrosis in liver and kidneys and to modulate inflammation in atherosclerosis. In this context, circulating and localized TGFBi and POSTN are differentially controlled by the Stabilins as their receptors. To assess Stab1 and Stab2 functions in inflammatory and fibrotic skin disease, topical Imiquimod (IMQ) was used to induce psoriasis-like skin lesions in mice and Bleomycin (BLM) was applied subcutaneously to induce scleroderma-like effects in the skin. The topical treatment with IMQ, as expected, led to psoriasis-like changes in the skin of mice, including increased epidermal thickness and significant weight loss. Clinical severity was reduced in Stab2-deficient compared to Stab1-deficient mice. We did not observe differential effects in the skin of Stabilin-deficient mice after bleomycin injection. Interestingly, treatment with IMQ led to a significant increase of Stabilin ligand TGFBi plasma levels in Stab2-/- mice, treatment with BLM resulted in a significant decrease in TGFBi levels in Stab1-/- mice. Overall, Stab1 and Stab2 deficiency resulted in minor alterations of the disease phenotypes accompanied by alterations of circulating ligands in the blood in response to the disease models. Stabilin-mediated clearance of TGFBi was altered in these disease processes. Taken together our results suggest that Stabilin deficiency-associated plasma alterations may interfere with preclinical disease severity and treatment responses in patients.

Preclinical techniques for drug discovery in psoriasis.

Psoriasis is a chronic, inflammatory, papulosquamous, noncontagious disease characterized by scaly, demarcated erythematous plaque, affecting skin, nails, and scalp. The IL-23/Th17 axis is the main operator in the development of psoriasis. Psoriasis is affecting worldwide, and new treatment options are urgently needed. Various local and systemic treatments are available for psoriasis but they only provide symptomatic relief because of numerous unknown mechanisms. Clinical trials demand overwhelming resources; therefore, drug development predominantly depends on the in-vivo, in-vitro, and ex-vivo techniques. Immediate attention is required to develop experimental techniques that completely imitate human psoriasis to assist drug development. This review portrays the various in-vivo, in-vitro, and ex-vivo techniques used in psoriasis research. It describes these techniques' characteristics, pathological presentations, and mechanisms. The experimental techniques of psoriasis provide significant information on disease progression mechanisms and possible therapeutic targets. However, until now, it has been challenging to invent a timely, affordable model that precisely imitates a human disease. Only the xenotransplantation model is reckoned as the closer, that mimics the complete genetic, and immunopathogenic event. Imiquimod-induced psoriasis and HaCat cell lines are popular among researchers because of their convenience, ease of use, and cost-effectiveness. There need to further improve the experimental techniques to best serve the disease imitation and meet the research goal.

Deucravacitinib and shikonin combination therapy ameliorates imiquimod-induced psoriasis in mice.

INTRODUCTION: TYK2 inhibitors and traditional natural drugs as promising drugs for psoriasis therapy are receiving increasing attention. They both affect different molecules of JAK/STAT pathway, but it is currently unclear whether their combination will enhance the effect on psoriasis. In this study, we used imiquimod (IMQ)-induced psoriasis mouse model to investigate the therapeutic effects of the combined administration of deucravacitinib (TYK2 inhibitor) and shikonin. METHODS: Aldara cream containing 5% IMQ was used to topically treat the dorsal skin of each mouse for a total of six consecutive days to induce psoriasis. The psoriasis area and severity index (PASI) scores were recorded every day. On the 7th day, skin tissues were taken for histopathological examination and the content of cytokines in skin were evaluated. The frequency of immune cells in peripheral blood, spleen and skin were detected through flow cytometry. RESULTS: Compared to the vehicle control group, the psoriasis symptoms and immune disorder improved significantly in the combination therapy group and deucravacitinib treatment group on the 7th day, and the expressions of p-STAT3 and Ki67 in skin were reduced as well. Moreover, the combined treatment of deucravacitinib and shikonin for psoriasis was superior to the monotherapy group, especially in inhibiting abnormal capillaries proliferation, reducing immune cells infiltration and decreasing the concentration of IL-12p70 in skin. CONCLUSION: The combination of deucravacitinib and shikonin is a promising clinical application.

Innate lymphoid cell-based immunomodulatory hydrogel microspheres containing Cutibacterium acnes extracellular vesicles for the treatment of psoriasis.

Psoriasis is a chronic skin inflammation influenced by dysregulated skin microbiota, with the role of microbiota in psoriasis gaining increasing prominence. Bacterial extracellular vesicles (bEVs) serve as crucial regulators in the interaction between hosts and microbiota. However, the mechanism underlying the therapeutic potential of bEVs from commensal bacteria in psoriasis remains unclear. Here, we investigated the therapeutic role of Cutibacterium acnes (C. acnes)-derived extracellular vesicles (CA-EVs) in psoriasis treatment. To prolong the active duration of CA-EVs, we encapsulated them in gelatin methacrylate (GelMA) to fabricate hydrogel microspheres (CA-EVs@GHM) with sustained release properties. As GelMA degraded, CA-EVs were gradually released, maintaining a high concentration in mouse skin even 96 h post-treatment. In human keratinocyte cells (HaCaT), CA-EVs@GHM enhanced resistance to Staphylococcus aureus (S. aureus), promoted proliferation and migration of HaCaT cells exposed to S. aureus, and significantly reduced the expression of inflammatory genes such as interleukin (IL)-6 and C-X-C motif chemokine ligand 8 (CXCL8). In vivo, CA-EVs@GHM, more potent than CA-EVs alone, markedly attenuated proinflammatory gene expression, including tumor necrosis factor (TNF), Il6, Il17a, Il22 and Il23a in imiquimod (IMQ)-induced psoriasis-like mice, and restored skin barrier function. 16S rRNA sequencing revealed that CA-EVs@GHM might provide therapeutic effects against psoriasis by restoring microbiota diversity on the back skin of mice, reducing Staphylococcus colonization, and augmenting lipid metabolism. Furthermore, flow cytometry analysis showed that CA-EVs@GHM prevented the conversion of type 2 innate lymphoid cells (ILC2) to type 3 innate lymphoid cells (ILC3) in psoriasis-like mouse skin, reducing the pathogenic ILC3 population and suppressing the secretion of IL-17 and IL-22. In summary, our findings demonstrate that the long-term sustained release of CA-EVs alleviated psoriasis symptoms by controlling the transformation of innate lymphoid cells (ILCs) subgroups and restoring skin microbiota homeostasis, thus offering a promising therapy for psoriasis treatment. STATEMENT OF SIGNIFICANCE: Cutibacterium acnes, which is reduced in psoriasis skin, has been reported to promote skin homeostasis by regulating immune balance. Compared to live bacteria, bacterial extracellular vesicles (bEVs) are less prone to toxicity and safety concerns. bEVs play a pivotal role in maintaining bacterial homeostasis and modulating the immune system. However,bEVs without sustained release materials are unable to function continuously in chronic diseases. Therefore, we utilized hydrogel microspheres to encapsulate Cutibacterium acnes (C. acnes)-derived extracellular vesicles (CA-EVs), enabling long term sustained release. Our findings indicate that, CA-EVs loaded gelatin methacrylate hydrogel microspheres (CA-EVs@GHM) showed superior therapeutic effects in treating psoriasis compared to CA-EVs. CA-EVs@GHM exhibited a more significant regulation of pathological type 3 innate lymphoid cells (ILC3) and skin microbiota, providing a promising approach for microbiota-derived extracellular vesicle therapy in the treatment of skin inflammation.

Imiquimod Reverses Chronic Toxoplasmosis-Associated Behavioral and Neurocognitive Anomalies in a Rat Model.

Toxoplasma gondii is the etiologic agent of toxoplasmosis, a highly prevalent parasitosis. Toxoplasma gondii (T. gondii) transits in the brain from acute (AT) to chronic toxoplasmosis (CT), under host immune control. In immunocompromised patients, reactivation of CT is potentially life-threatening. Behavioral and neurological complications have been associated with CT. Furthermore, an effective treatment targeting CT is still lacking. We previously reported the efficacy of imiquimod against CT. Here, we demonstrate the molecular effects of imiquimod or imiquimod followed by the clinically used combination of sulfadiazine and pyrimethamine (SDZ + PYR) on CT-associated behavior in a rat model. Imiquimod decreased the number of cysts in the brains of chronically infected rats due to an induced reactivation of bradyzoites into tachyzoites. Importantly, this decrease was more pronounced in rats treated with imiquimod followed by SDZ + PYR. Rats chronically infected with T. gondii exhibited an anxiety-like behavior. Notably, treatment with imiquimod reversed this behavior aberrancy, with even a more pronounced effect with imiquimod followed by SDZ/PYR. Similarly, rats chronically infected with T. gondii exhibited learning deficits, and imiquimod alone or followed by SDZ/PYR reversed this behavior. Our results enhance our knowledge of the implications of CT on behavioral aberrancies and highlight the potency of imiquimod followed by SDZ + PYR on these CT-associated complications.

Improvement effects of a novel Chinese herbal formula in imiquimod and IL-23-stimulated mouse models of psoriasis.

BACKGROUND: Psoriasis is a long-term inflammatory skin disease. A novel herbal formula containing nine Chinese herbal medicines, named Inflammation Skin Disease Formula (ISDF), has been prescribed in clinics for decades. AIMS: To investigate the efficacy and action mechanisms of ISDF on psoriasis using imiquimod (IMQ) and Interleukin-23 (IL-23)-induced models in mice and reveal the pharmacokinetics profile of ISDF in rats. METHODS: Topical administration of IMQ and intradermal injection with IL-23 respectively induced skin lesions like psoriasis on the dorsal area of Balb/c and C57 mice. The mice's body weight, skin thickness, and psoriasis area and severity index (PASI) were assessed weekly. SD rats were used in the pharmacokinetics study and the contents of berberine and baicalin were determined. RESULTS: The PASI scores and epidermal thickness of mice were markedly decreased after ISDF treatment in both models. ISDF treatment significantly decreased the contents of IL-17A and IL-22 in the serum of IMQ- and IL-23-treated mice. Importantly, ISDF markedly downregulated IL-4, IL-6, IL-1ß, and tumor necrosis factor α (TNF-α) gene expression, and the phosphorylation of NF-κB p65, JNK, ERKs and MAPK p38 in IMQ-treated mice. The protein phosphorylation of Jak1, Jak2, Tyk2 and Stat3 was significantly mitigated in the ISDF-treated groups. The absorption of baicalin and berberine of ISDF through the gastrointestinal tract of rats was limited, and their distribution and metabolism in rats were also very slow, which suggested ISDF could be used in the long-term application. CONCLUSIONS: ISDF has a strong anti-psoriatic therapeutic effect on mouse models induced with psoriasis through IMQ and IL-23, which is achieved by inhibiting the activation of the Jak/Stat3-activated IL-23/Th17 axis and the downstream NF-κB signalling and MAPK signalling pathways. ISDF holds great potential to be a therapy for psoriasis and should be further developed for this purpose.

Fabrication and characterization of apremilast-loaded zinc oxide-mesoporous silica nanoparticles for psoriasis treatment.

Aim: The study was aimed to formulate and evaluate apremilast-loaded zinc oxide-mesoporous silica nanoparticles for treatment of psoriasis. Materials & methods: Mesoporous silica nanoparticles were prepared by using sol-gel method and evaluated for particle size, in vitro drug release, in vitro cytotoxicity study and in vivo pharmacodynamic study. Results: The synthesized mesoporous silica nanoparticles showed particle size of 319.9 ± 3.9 nm, with 24 ± 0.217% of loading capacity. In vitro cytotoxicity study on A-431 cell line showed increased anti-psoriatic activity of apremilast-loaded zinc oxide-mesoporous silica nanoparticles. In vivo pharmacodynamic study and histological studies showed improved efficacy of drug in imiquimod-induced psoriasis mice model. Conclusion: The apremilast-loaded zinc oxide-mesoporous silica nanoparticles showed improved therapeutic efficacy, suggesting that they are promising approach for topical treatment of psoriasis.

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Successful management of chromoblastomycosis utilizing conventional antifungal agents and imiquimod therapy.

Chromoblastomycosis (CBM), a chronic fungal infection affecting the skin and subcutaneous tissues, is predominantly caused by dematiaceous fungi in tropical and subtropical areas. Characteristically, CBM presents as plaques and nodules, often leading to scarring post-healing. Besides traditional diagnostic methods such as fungal microscopy, culture, and histopathology, dermatoscopy and reflectance confocal microscopy can aid in diagnosis. The treatment of CBM is an extended and protracted process. Imiquimod, acting as an immune response modifier, boosts the host's immune response against CBM, and controls scar hyperplasia, thereby reducing the treatment duration. We present a case of CBM in Guangdong with characteristic reflectance confocal microscopy manifestations, effectively managed through a combination of itraconazole, terbinafine, and imiquimod, shedding light on novel strategies for managing this challenging condition.

Lentigo Maligna Treatment-An Update.

Lentigo maligna (LM) is a melanoma in situ that is prevalent in chronically sun-damaged skin. Characterized by a slow growth pattern and high mutation rates due to chronic UV exposure, LM poses diagnostic and therapeutic challenges, particularly given its tendency to mimic other skin lesions and its occurrence in cosmetically sensitive areas. Its diagnosis is based on an integrated approach using dermoscopy and reflectance confocal microscopy (RCM). Despite its slow progression, LM can evolve into lentigo maligna melanoma (LMM), making its treatment necessary. Treatment modalities encompass both surgical and non-surgical methods. Surgical treatments like Wide Local Excision (WLE) and Mohs Micrographic Surgery (MMS) aim for clear histological margins. WLE, a standard melanoma surgery, faces challenges from LM's subclinical extensions, which increase the recurrence risk. MMS, effective for large or poorly defined lesions, is defined by precise margin control while considering cosmetic outcomes. Non-surgical options, including radiotherapy and imiquimod, are alternatives for non-surgical candidates. Radiotherapy has been effective since the 1950s, offering good control and cosmetic results, especially for older patients. Imiquimod, an immunomodulator, shows promise in treating LM, though its application remains off-label. The increasing incidence of LM/LMM necessitates a balance in treatment choices to minimize recurrence and maintain cosmetic integrity. A multidisciplinary approach, integrating clinical examination with dermoscopy and RCM and histological assessment, is essential for accurate diagnosis and effective LM management.

Low-concentration imiquimod treatment promotes enhanced skin barrier functions through epidermal melanization reaction regulation.

The primary function of the skin is to form a mechanical, permeability, antimicrobial, and ultraviolet radiation barrier, which is essential for maintaining physiological homeostasis. Our previous studies demonstrated that cutaneous pigmentation could promote skin barrier function in addition to providing anti-ultraviolet irradiation defense. The present study aimed to develop a new regimen that enhances skin barrier function by regulating skin pigmentation using low-concentration imiquimod. Results showed that topical application of low-concentration imiquimod effectively induced skin hyperpigmentation in the dorsal skin and external ear of mice without inducing inflammatory cell infiltration. An in vitro study also revealed that low-concentration imiquimod did not induce any cytotoxic effects on melanoma cells but triggered excessive melanin synthesis. In coculture systems, low-concentration imiquimod was noted to increase tyrosinase activity in a broader cellular context, revealing the potential role of neighboring cells in melanin production. The next-generation sequencing result indicated that PKCη and Dnm3 might regulate melanin synthesis and release during imiquimod treatment. Overall, our study presents new insights into the regulation of melanin production by low-concentration imiquimod, both in a mice model and cultured cells. Furthermore, our study highlights the potential benefits of imiquimod in promoting melanin synthesis without causing skin disruptions or inducing inflammation, validating its potential to serve as a method for enhancing skin barrier functions by regulating the epidermal melanization reaction.

Immunomodulating effects of the single bacterial strain therapy EDP1815 on innate and adaptive immune challenge responses - a randomized, placebo-controlled clinical trial.

The gut microbiome can modulate systemic inflammation and is therefore target for immunomodulation. Immunomodulating effects of EDP1815, a bacterial commensal strain of Prevotella histicola, were studied in healthy participants. Effects on adaptive immunity were evaluated by a neo-antigen challenge with keyhole limpet haemocyanin (KLH), while effects on innate immunity were evaluated by topical toll-like receptor 7 (TLR7) agonist imiquimod. Capsules with two enteric coating levels (EC1, EC2) were compared. Thirty-six healthy participants were included and received a daily dose of 8 × 1010 cells EDP1815-EC1, EDP1815-EC2 or placebo (randomization 1:1:1) for 60 days. They received KLH vaccinations at days 8, 24 and 36, with intradermal skin challenge at day 57. KLH challenge outcomes were antibody levels, and skin blood flow and erythema after skin challenge, measured by imaging techniques. Imiquimod administration started at day 57, for 72 h. Outcomes consisted of imaging measurements similar to the KLH challenge, and the influx of inflammatory cells and cytokines in blister fluid. There was no effect of EDP1815 treatment on the KLH challenge, neither on the imaging outcomes of the imiquimod challenge. There was a consistently lower influx of inflammatory cells in the blister fluid of EDP1815-treated participants (neutrophils, p = 0.016; granulocytes, p = 0.024), more pronounced in EC1. There was a lower influx of interleukin [IL]-1ß, IL-6, IL-8, IL-10, interferon [IFN]-γ and tumour necrosis factor in blister fluid of EDP1815-treated participants. EDP1815 had immunomodulatory effects on the innate immune response driven by imiquimod, but no effect on the KLH challenge was observed. Trial registration number: NCT05682222; date: 22 July 2022.

Macrophage Functions in Psoriasis: Lessons from Mouse Models.

Psoriasis is a systemic autoimmune/autoinflammatory disease that can be well studied in established mouse models. Skin-resident macrophages are classified into epidermal Langerhans cells and dermal macrophages and are involved in innate immunity, orchestration of adaptive immunity, and maintenance of tissue homeostasis due to their ability to constantly shift their phenotype and adapt to the current microenvironment. Consequently, both macrophage populations play dual roles in psoriasis. In some circumstances, pro-inflammatory activated macrophages and Langerhans cells trigger psoriatic inflammation, while in other cases their anti-inflammatory stimulation results in amelioration of the disease. These features make macrophages interesting candidates for modern therapeutic strategies. Owing to the significant progress in knowledge, our review article summarizes current achievements and indicates future research directions to better understand the function of macrophages in psoriasis.

Nail Squamous Cell Papilloma: A Rare Case Report.

Introduction: Squamous cell papilloma is a benign tumor whose pathogenesis is generally related to the human papillomavirus. Despite affecting several organs, we did not find cases reported in the nails. Case Presentation: A 67-year-old female presented with a painful lesion in the nail of the right hallux that started in 2021, with an erythematous appearance evolving to black and expansive growth. Due to the evolution and symptoms, she opted for excision, with a histopathological report of squamous cell papilloma. Complementary treatment with imiquimod was performed, with good healing and pain control. Discussion: Due to the lack of previous reports, treatment was based on therapeutic options for papillomas located in other regions. Excision was performed, followed by application of imiquimod with good response. The prognosis is favorable; however, further studies are needed to elucidate the diagnosis and management of nail squamous cell papilloma.

Extramammary Paget Disease. Part II. Evidence-based Approach to Management.

Extramammary Paget disease is a rare cutaneous malignancy that most commonly affects the genitals, perianal area, and axilla of elderly patients. Delays in care often lead to high levels of disease burden for patients. Thus, evidence-based recommendations are paramount in mitigating morbidity and mortality for this unique patient population. This 2-part continuing medical education series provides a complete picture of extramammary Paget disease. Part 2 of this continuing medical education series focuses on the complex management of extramammary Paget disease including surgical and non-invasive therapies, as well as novel approaches for advanced disease.

Modulation of sHLA-G, PD-1, and PD-L1 Expression in Cervical Lesions Following Imiquimod Treatment and Its Association with Treatment Success.

(1) Background: Cervical intraepithelial neoplasia (CIN) is a precancerous condition linked to human papillomavirus (HPV) infection, often necessitating surgical interventions carrying the risk of subsequent preterm births. This study explores the potential of imiquimod (IMQ), as a non-invasive alternative treatment. The focus is on understanding IMQ impact on immune checkpoint molecules, particularly PD-1, PD-L1, and sHLA-G, which play pivotal roles in shaping immune responses and cancer progression. (2) Methods: Forty-three patients diagnosed with a high-risk squamous intraepithelial lesion (HSIL, p16-positive) self-applied 5% IMQ encapsulated in sachets containing 250 g of cream into the vaginal cavity three times a week for 16 weeks. The impact of IMQ therapy on cervical lesion regression was assessed through immunohistochemistry (IHC), examining changes in sHLA-G, PD-L1, and PD-1 levels. The antiviral activity of IMQ was evaluated through HPV-E7 immunofluorescence. Ethical considerations were adhered to, and the research methods were based on a previously approved clinical trial (clinicaltrials.gov Identifier: NCT04859361). (3) Results: IMQ treatment demonstrated efficacy, leading to lesion regression. sHLA-G levels in CIN before starting IMQ application were associated with unsuccessful treatment (p = 0.0036). IMQ did not significantly alter the expression of PD-1. We observed a decrease in PD-L1 levels in those who were successfully treated (p = 0.0509) and a reduction in HPV burden. (4) Conclusions: IMQ exhibits promise as a non-invasive treatment for CIN, emphasising its potential to modulate the immune microenvironment. Baseline sHLA-G levels emerge as potential predictors of treatment response. Understanding the nuanced dynamics of immune checkpoints sheds light on IMQ mechanism of action. Further exploration is warranted to decipher the intricate mechanisms underlying IMQ treatment in the context of cervical lesions.

Imiquimod Is Effective in Reducing Cervical Intraepithelial Neoplasia: A Systematic Review and Meta-Analysis.

INTRODUCTION: Topical Imiquimod is an immune response modifier approved for the off-label use of vulvar intraepithelial neoplasia. We conducted this systematic review and meta-analysis to investigate the efficacy and safety of Imiquimod in treating cervical intraepithelial neoplasia (CIN) and human papillomavirus (HPV)-positive patients. METHODS: The study was prospectively registered (CRD420222870) and involved a comprehensive systematic search of five medical databases on 10 October 2022. We included articles that assessed the use of Imiquimod in cervical dysplasia and HPV-positive patients. Pooled proportions, risk ratios (RRs), and corresponding 95% confidence intervals (CIs) were calculated using a random effects model to generate summary estimates. Statistical heterogeneity was assessed using I2 tested by the Cochran Q tests. RESULTS: Eight articles reported on 398 patients who received Imiquimod out of 672 patients. Among CIN-2-3 patients, we observed a pooled regression rate of 61% (CI: 0.46-0.75; I2: 77%). When compared, Imiquimod was inferior to conization (RR: 0.62; CI: 0.42-0.92; I2: 64%). The HPV clearance rate in women who completed Imiquimod treatment was 60% (CI: 0.31-0.81; I2: 57%). The majority of side effects reported were mild to moderate in severity. CONCLUSIONS: Our findings indicate that topical Imiquimod is safe and effective in reducing cervical intraepithelial neoplasia and promoting HPV clearance. However, it was found to be inferior compared to conization. Imiquimod could be considered a potential medication for high-grade CIN patients and should be incorporated into guidelines for treating cervical dysplasia.

Interferon-Alpha Induces Psoriatic Inflammation in Mice by Phosphorylating FOXO3.

Psoriasis is a chronic, immune-mediated inflammatory skin disease characterized by epidermal thickening and inflammatory cell infiltration. Excessive proliferation of keratinocytes and resistance to apoptosis lead to thickening of the epidermis. Plasmacytoid dendritic cells are involved in the occurrence of psoriasis mainly by secreting interferon-alpha (IFN-α). IFN-α is a glycoprotein with antiviral, antitumor, and immunomodulatory effects, but its role in psoriasis remains unclear. In this investigation, a mild psoriatic phenotype was observed in mice upon topical application of IFN-α cream, and the inflammation was exacerbated when combined with imiquimod (IMQ). Immunohistochemical analyses demonstrated that IFN-α induces psoriatic inflammation in mice by stimulating phosphorylation of forkhead box O3, consistent with the involvement of this protein in cell proliferation, apoptosis, and inflammation. Our results suggested that topical IFN-α caused psoriatic inflammation and that the psoriatic inflammation was exacerbated by the combination of IFN-α and IMQ, possibly due to the dysfunction of forkhead box O3.

The regulation of the PD-1/PD-L1 pathway in imiquimod-induced chronic psoriasis itch and itch sensitization in mouse.

PD-1/PD-L1 inhibitors have been demonstrated to induce itch in both humans and experimental animals. However, whether the PD-1/PD-L1 pathway is involved in the regulation of chronic psoriatic itch remains unclear. This study aimed to investigate the role of the PD-1/PD-L1 pathway in imiquimod-induced chronic psoriatic itch. The intradermal injection of PD-L1 in the nape of neck significantly alleviated chronic psoriatic itch in imiquimod-treated skin. Additionally, we observed that spontaneous scratching behavior induced by imiquimod disappeared on day 21. Still, intradermal injection of PD-1/PD-L1 inhibitors could induce more spontaneous scratching for over a month, indicating that imiquimod-treated skin remained in an itch sensitization state after the spontaneous scratching behavior disappeared. During this period, there was a significant increase in PD-1 receptor expression in both the imiquimod-treated skin and the spinal dorsal horn in mice, accompanied by significant activation of microglia in the spinal dorsal horn. These findings suggest the potential involvement of the peripheral and central PD-1/PD-L1 pathways in regulating chronic itch and itch sensitization induced by imiquimod.