Imiquimod-induced Psoriasis In Mice Research Articles

Oral Exposure to Low Concentration of Fumonisin B2, but Not Fumonisin B1, Significantly Exacerbates the Pathophysiology of Imiquimod-Induced Psoriasis in Mice.

This study aimed to determine whether oral fumonisin exposure contributes to the development of psoriasis. Oral administration of fumonisin B1 (FB1, 0.1 mg/kg) or fumonisin B2 (FB2, 0.1 mg/kg) was conducted for 10 days, in addition to the induction of psoriatic symptoms through topical application of 5% imiquimod cream from day 6 to day 10 (5 days) in female BALB/c mice. The results demonstrated that oral administration of FB2 significantly exacerbated psoriatic symptoms, including skin thickness, itching behavior, transepidermal water loss, immune cell infiltration in the dermis, and proinflammatory cytokine production. However, no changes were observed following exposure to FB1. Our results confirm that oral exposure to FB2 adversely affects the pathogenesis of psoriasis by increasing skin thickness and impairing barrier function.

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

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. 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. 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. The combination of deucravacitinib and shikonin is a promising clinical application.

Anti-proliferative, Anti-oxidant and Anti-inflammatory Effects of Topical Rutin on Imiquimod-Induced Psoriasis in Mice

Anti-proliferative, Anti-oxidant and Anti-inflammatory Effects of Topical Rutin on Imiquimod-Induced Psoriasis in Mice

Ethanol extract of Herpetospermum caudigerum Wall ameliorates psoriasis-like skin inflammation and promotes degradation of keratinocyte-derived ICAM-1 and CXCL9

ObjectiveTo explore whether the ethanol extract of Herpetospermum caudigerum Wall (EHC), a Xizang medicinal plant traditionally used for treating liver diseases, can improve imiquimod-induced psoriasis-like skin inflammation. MethodsImmunohistochemistry and immunofluorescence staining were used to determine the effects of topical EHC use in vivo on the skin pathology of imiquimod-induced psoriasis in mice. The protein levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-17A (IL-17A) in mouse skin samples were examined using immunohistochemical staining. In vitro, IFN-γ-induced HaCaT cells with or without EHC treatment were used to evaluate the expression of keratinocyte-derived intercellular cell adhesion molecule-1 (ICAM-1) and chemokine CXC ligand 9 (CXCL9) using Western blotting and reverse transcription-quantitative polymerase chain reaction. The protein synthesis inhibitor cycloheximide and proteasome inhibitor MG132 were utilized to validate the EHC-mediated mechanism underlying degradation of ICAM-1 and CXCL9. ResultsEHC improved inflammation in the imiquimod-induced psoriasis mouse model and reduced the levels of IFN-γ, TNF-α, and IL-17A in psoriatic lesions. Treatment with EHC also suppressed ICAM-1 and CXCL9 in epidermal keratinocytes. Further mechanistic studies revealed that EHC suppressed keratinocyte-derived ICAM-1 and CXCL9 by promoting ubiquitin–proteasome-mediated protein degradation rather than transcriptional repression. Seven primary compounds including ehletianol C, dehydrodiconiferyl alcohol, herpetrione, herpetin, herpetotriol, herpetetrone and herpetetrol were identified from the EHC using ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry. ConclusionTopical application of EHC ameliorates psoriasis-like skin symptoms and improves the inflammation at the lesion sites.Please cite this article as: Zhong Y, Zhang BW, Li JT, Zeng X, Pei JX, Zhang YM, Yang YX, Li FL, Deng Y, Zhao Q. Ethanol extract of Herpetospermum caudigerum Wall ameliorates psoriasis-like skin inflammation and promotes degradation of keratinocyte-derived ICAM-1 and CXCL9. J Integr Med. 2023; Epub ahead of print.

Shikonin promotes ferroptosis in HaCaT cells through Nrf2 and alleviates imiquimod-induced psoriasis in mice

Psoriasis is one kind of autoimmune skin disease without efficiency cure. Shikonin (SHK) is a potential drug for psoriasis treatment. Recent study suggested that ferroptosis involved in the pathological process of psoriasis. This study proved the beneficial effect of SHK with an imiquimod (IMQ) induced psoriatic model mice, and studied the ferroptosis regulative mechanism of SHK with a HaCaT cells assay in vitro. In the study, it also found that SHK treatment significantly improved imiquimod (IMQ)-induced psoriasis symptoms in mice, attenuated the production of inflammatory cytokines, including interleukin (IL)-6, IL-17, and tumor necrosis factor-alpha (i.e., TNF-α), and strongly inhibited macrophage infiltration in inflamed psoriatic skin. SHK impacted HaCaT cells (a human keratinocyte cell line) viability by enhancing intracellular and mitochondrial ferrous and lipid peroxidation levels by regulating expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), nuclear receptor coactivator 4 (NCOA4) and glutathione peroxidase 4 (GPX4) which could be reversed by iron chelating agent. and in psoriatic dermatitis. However, this study found the reversing capability of low dose SHK on LPS inhibited GPX4 and Nrf2 expression, which was identity to that in psoriatic dermatitis. To conclude, SHK inhibited ferroptosis in psoriatic skin by reducing inflammation, ameliorating oxidative stress and iron accumulation. Nrf2 and GPX4 might be the two major targets of SHK in psoriatic skin lesion. Our study highly lighted the basic biological mechanism of SHK on ferroptosis regulation.

Co-induced allergic response to an unrelated allergen exacerbates imiquimod-induced psoriasis in mice.

Psoriasis is classically regarded as a Th1 response-dominant disease believed to be antagonized by the Th2 response, which is responsible for allergic diseases, such as atopic dermatitis. The roles of these responses in psoriasis and the relationship between psoriasis and atopic dermatitis have received increasing attention because it is estimated that more than one million patients are concomitantly affected by psoriasis and atopic dermatitis. To address this, we attempted to determine the characteristics of imiquimod-induced psoriasiform lesions in mice with a concomitant allergic response after co-application of the unrelated allergen ovalbumin onto the skin. Imiquimod cream containing ovalbumin was successively applied to the right back skin of hairless HR female mice. Psoriasiform scores were determined for 11 days, and then, the resected skin thickness, spleen weight, and serum antibody levels were examined. In some experiments, mice were allowed free access to ovalbumin-containing water for 10 days before skin application to induce oral tolerance. Imiquimod cream induced psoriasis, and its severity increased upon simultaneous ovalbumin treatment. Increases in anti-ovalbumin IgG2a levels, a Th1 response indicator, and IgG1 and IgE levels, Th2 response indicators, were mediated by ovalbumin addition. Oral tolerance against ovalbumin effectively decreased ovalbumin-exacerbated imiquimod-induced psoriasis, in parallel with a decrease in levels of anti-ovalbumin antibodies. These results suggest that the concomitant allergic response induced by ovalbumin application exacerbates imiquimod-induced psoriasis. This implies that allergic responses to unrelated allergens might exacerbate psoriasis in humans and that modulating such responses could be an effective new approach to treat psoriasis.

Nutraceutical combination ameliorates imiquimod-induced psoriasis in mice.

Psoriasis is a chronic inflammatory skin disease that affects both localized and systemic regions of the body. This condition is characterized by the hyperproliferation of keratinocytes, resulting in skin thickening, scaling, and erythema. The severity of psoriasis depends on the extent of skin involvement, the location of the infection, and the symptoms that the person exhibits. While no cure exists, conventional therapies such as topical and systemic drugs are generally used to manage the exacerbation of symptoms. However, chronic use and overdose can lead to other severe adverse effects. Therefore, scientists and researchers are exploring potential nutraceuticals that can be considered as an alternative source of management for psoriasis. Current research aims to use different combinations of natural compounds like cannabidiol, myo-inositol, eicosapentaenoic acid, and krill oil to study the effect of these compounds in the prevention and treatment of psoriasis in the imiquimod (IMQ)-induced psoriatic mice model. The Psoriasis Area Severity Index (PASI) scoring system is used to analyze skin thickness, scales, and erythema. The results indicate that the krill oil combined with the cannabidiol and myo-inositol shows better results than other nutraceutical combinations. In the future, the natural products of krill oil can be combined with cannabidiol and myo-inositol to create an improved alternative to existing steroidal and nonsteroidal anti-inflammatory drugs for psoriasis treatment.

The therapeutic effect of glycyrrhizic acid compound ointment on imiquimod-induced psoriasis-like disease in mice.

Glycyrrhetinic acid, a drug with anti-inflammatory effects, enhanced the activity of antipsoriatic efficacy. In this research, an ointment with glycyrrhetinic acid was prepaired as the major component and several other herbal monomers (astilbin, osthole, and momordin Ic) have antipsoriatic activity as minor components. Then an Imiquimod-induced psoriasis-like mouse model was established and the damaged skin condition of the administered group, the changes in the spleen index and the secretion of inflammatory factors in mouse skin were observed. Calcipotriol ointment was used as a positive control to compare the efficacy. Glycyrrhizic acid compound ointment significantly improved imiquimod-induced psoriasis in mice and reduced the secretion of TNF-α, IL-12, IL-17, and IL-23 in mouse skin, and showed a stronger therapeutic effect than calcipotriol ointment. Calcipotriol ointment did not significantly alleviate imiquimod-induced splenomegaly and did not significantly reduce the expression of IL-17 and IL-23 in mouse skin. Glycyrrhetinic acid compound ointment was more effective than calcipotriol and was dose-dependent in the treatment of imiquimod-induced psoriatic dermatitis in mice. Meanwhile,calcipotriol was not suitable for the treatment of Imiquimod -induced psoriasis-like mice.

Discovery of novel triazine derivatives as potent retinoic acid receptor-related orphan receptor γt (RORγt) inverse agonists

Retinoic Acid Receptor-Related Orphan Receptor γt (RORγt) has been exploited as a promising target for the new small molecule therapeutics to treat inflammatory and autoimmune diseases via modulating the interleukin-17 (IL-17) production by T helper 17 (Th17) cells. Herein, we reported a series of triazine-based derivatives as novel RORγt inverse agonists. By screening of our in-house compound library, the hit compound 1 was identified with weak RORγt inhibitory activity. Subsequently, we engineered detailed structural modifications to explore the structure-activity relationships (SARs) of triazines derivatives, which led to discovery of a number of potent RORγt inverse agonists with IC50 values in the range of 7 nM–50 nM in RORγt dual FRET assay. Among them, compound 14g displayed potent RORγt inverse agonistic activity with an IC50 value of 22.9 nM in dual FRET assay. In a cell-based reporter gene assay, compound 14g showed an IC50 value of 0.428 μM and maximum inhibition rate of 108.9%. Compound 14g also exhibited good metabolic stability and a decent pharmacokinetic profile with a low clearance (CL = 0.229 L/h/kg) and a reasonable oral exposure (AUC0-Last = 5058 ng/mL*h). Most importantly, 14g alleviated the severity of imiquimod-induced psoriasis in mice. Taken together, triazine-based derivatives represent a new chemical class of RORγt inverse agonists as potential therapeutic agents against autoimmune diseases.

Separation, characterization and anti-psoriasis effect of self-assembled nanoparticles from Shaoyao Gancao Decoction

This study aims to separate and characterize self-assembled nanoparticles(SAN) from Shaoyao Gancao Decoction(SGD) and determine the content of active compounds. Further, we aimed to observe the therapeutic effect of SGD-SAN on imiquimod-induced psoriasis in mice. The separation of SGD was performed by dialysis, and the separation process was optimized by single factor experiment. The SGD-SAN isolated under the optimal process was characterized, and the content of gallic acid, albiflorin, paeoniflorin, liquiritin, isoliquiritin apioside, isoliquiritin, and glycyrrhizic acid in each part of SGD was determined by HPLC. In the animal experiment, mice were assigned into a normal group, a model group, a methotrexate group(0.001 g·kg~(-1)), and SGD, SGD sediment, SGD dialysate, and SGD-SAN groups of different doses(1, 2, and 4 g·kg~(-1)) respectively. The psoriasis grade of mice was evaluated based on the pathological changes of skin lesions, the content of inflammatory cytokines, organ index and other indicators. The results showed that SAN obtained by centrifugation at 13 000 r·min~(-1) for 30 min was stable after dialysis for 4 times, which were uniform spherical nanoparticles with the particle size of(164.43±1.34) nm, the polydispersity index of(0.28±0.05), and the Zeta potential of(-12.35±0.80) mV. The active compound content accounted for more than 70% of SGD. Compared with the model group, SAN and SGD decreased the skin lesion score, spleen index, and inflammatory cytokine levels(P<0.05 or P<0.01) and alleviated the skin thickening and infiltration of inflammatory cells. However, the sediment group and the dialysate group had no obvious effect. SGD showed a good therapeutic effect on imiquimod-induced psoriasis in mice, and SAN demonstrated the effect equivalent to SGD in a dose-dependent manner. Therefore, we conclude that the SAN formed during decocting is the main active form of SGD, which can lower the levels of inflammatory cytokines, promote the normal differentiation of keratinocytes, and reduce the infiltration of inflammatory cells in the treatment of psoriasis lesions in mice.

Fufang Shengdi mixture alleviates psoriasis-like skin inflammation via promoting Annexin-A proteins expression

Ethnopharmacological relevanceTraditional Chinese medicine believes that “blood fever” is an important cause of psoriasis. Fufang Shengdi mixture (FFSD), based on the Hongban Decoction, is composed of Rehmannia glutinosa (Gaertn.) DC., Raw gypsum (Chinese: Sheng Shi Gao), and Lonicera japonica Thunb (Caprifoliaceae). FFSD has effects on nourishing Yin, clearing heat, connecting collaterals, and cooling blood. In modern medical explanation, FFSD has the effects of anti-inflammatory and immunosuppression. Our study proved that FFSD can suppress immunity and ameliorate the symptoms of imiquimod-induced psoriasis in mice. Aim of the studyThis study evaluated the efficacy and possible mechanism of FFSD in psoriasis mice. Methods and materialsFirst, the main components of FFSD were analyzed using high-performance liquid chromatography-tandem high-resolution mass spectrometry (HPLC-HRMS). An imiquimod (IMQ)-induced psoriasis mouse model was used to evaluate the efficacy of FFSD orally. Psoriasis area and severity index (PASI) scores were recorded throughout the course of the mice to reflect the severity of psoriasis. Hematoxylin-eosin staining was used to observe the pathological changes in skin lesions. Enzyme-linked immunosorbent assay (ELISA) was performed to test the level of IFN-γ and TNF-α in plasma. To further investigate the immunopharmacological effect of FFSD, we used chicken ovalbumin (OVA) to induce immunoreaction in mice. ELISA was used to detect the levels of anti-OVA antibody, IFN-γ and TNF-α in mice. Flow cytometry was performed to quantify the ratio of cell types in peripheral blood mononuclear cells (PBMCs) to evaluate the effect of FFSD on immunosuppression. Proteomics and bioinformatics analyzes were performed to find the regulation pathway of the immunosuppressive effect of FFSD. Finally, quantitative PCR (qPCR) and immunohistochemistry were used to measure the upregulation of Annexin-A proteins (ANXAs) in the skin lesion tissue of IMQ-induced mouse. ResultsOn the basis of knowing the composition of FFSD, we first proved the efficacy of FFSD in alleviating IMQ-induced psoriasis in mice. Second, we further clarified the pharmacological effect of FFSD on immunosuppression via OVA-induced mice. Subsequently, it was found that the significant up-regulation of ANXAs was caused by FFSD through proteomics analysis, and the finding was proved in the IMQ-induced psoriasis mouse model. ConclusionsThis study elucidates the immunosuppressive pharmacological effect of FFSD on improving psoriasis through up-regulating ANXAs.

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

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.

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.

Development and Pharmacological assessment of dehydrozingerone gel formulation on imiquimod-induced psoriasis in mice

Psoriasis is a chronic inflammatory autoimmune skin disorder, generally due to the interaction between genetic, environmental and immune factors. It is mainly associated with HLA locus (HLA-C), particularly with HLA-Cw* 0602 allele. The stimulation of T-cell induces hyper-proliferation of keratinocytes, which results in psoriatic lesions. Psoriatic patients are usually treated with medications that block TNF-α function. Complexities in the pathogenesis of psoriasis have been a challenge to develop an effective treatment regimen. Thus, studies are still underway for exploring drugs to treat psoriasis. Researchers have reported the antioxidant, antibacterial and anti-inflammatory properties of the structural half analogue of curcumin, dehydrozingerone (DHZ). Pre-clinical studies have reported the wound healing and anti-inflammatory properties of this compound. DHZ is also capable of blocking TNF alpha, which is one of the early cytokines implicated in psoriasis. Therefore, the current study has been proposed to explore the effect of DHZ to reduce psoriatic like lesions in imiquimod-induced psoriasis in mice. Upon the development of psoriatic like lesions, clinical scoring for scaling and erythema was taken on a scale of 0-4. DHZ has shown a significant reduction of scaling in comparison to the disease control, denoting the effectiveness of the test drug.

Anti-inflammatory Effects of Topically Applied Azilsartan in a Mouse Model of Imiquimod-induced Psoriasis

Background: Many studies showed a possible exacerbation of psoriasis after exposure to angiotensin receptor antagonists. Azilsartan is a competitive angiotensin II receptor antagonist and has anti-inflammatory effects in various inflammatory disorders. Objective: Investigate dose-dependent effects of topical Azilsartan on Imiquimod-induced psoriasis in mice. Methods: Forty-eight mice are allocated into six groups (8 mice per group). They all received Imiquimod for the induction of psoriasis (except Group I, a negative control group). Group II (Induction group) received petroleum gel for six days after induction with Imiquimod. The other groups (III, IV, V, and VI) were given Clobetasol propionate 0.05, 1% Azilsartan, 3% Azilsartan, and a combination of 3% Azilsartan and 0.05% Clobetasol propionate ointments, respectively once daily for six days after induction. Results: Azilsartan decreased psoriasis area severity index (PASI) score and attenuated the histological manifestations after induction. It significantly decreased the serum and tissue levels of the inflammatory biomarkers (TNF-α, IL-17, IL-23, and NF-Kβ), especially when used as an add-on therapy to Clobetasol. Conclusion: Topically-applied Azilsartan shows anti-psoriatic effects in Imiquimod-induced psoriasis in mice via anti-inflammatory and anti-proliferative activities.

Free Fatty Acid Receptor 4 (FFA4) Activation Ameliorates Imiquimod-Induced Psoriasis in Mice

Dietary supplementation with n-3 polyunsaturated fatty acids (n-3 PUFA) has been used as an adjunct therapy for psoriasis due to its anti-inflammatory properties. Free fatty acid receptor 4 (FFA4 or GPR120) is a receptor-sensing n-3 PUFA. In the present study, we examined whether FFA4 acted as a therapeutic target for n-3 PUFA in psoriasis therapy. Experimentally, psoriasis-like skin lesions were induced by treatment with imiquimod for 6 consecutive days. A selective FFA4 agonist, Compound A (30 mg/kg), was used in FFA4 WT and FFA4 KO mice. Imiquimod-induced psoriasis-like skin lesions, which present as erythematous papules and plaques with silver scaling, as well as markedly elevated IL-17/IL-23 cytokine levels in skin tissues, were significantly suppressed by Compound A in FFA4 WT mice, but not in FFA4 KO mice. Enlarged lymph nodes and spleens, as well as imiquimod-induced, elevated IL-17/IL-23 cytokine levels, were also strongly suppressed by Compound A in FFA4 WT mice, but not in FFA4 KO mice. Imiquimod-induced increases in the CD4+IL-17A+ T cell population in lymph nodes and spleens were suppressed by Compound A treatment in FFA4 WT mice; however, this was not seen in FFA4 KO mice. Furthermore, compound A suppressed the differentiation of CD4+ naïve T cells from splenocytes into TH17 cells in an FFA4-dependent manner. In conclusion, we demonstrated that the activation of FFA4 ameliorates imiquimod-induced psoriasis, and the suppression of the differentiation of TH17 cells may partly contribute to its efficacy. Therefore, we suggest that FFA4 could be a therapeutic target for psoriasis therapy.

Topical Application of Tetrandrine Nanoemulsion Promotes the Expansion of CD4+Foxp3+ Regulatory T Cells and Alleviates Imiquimod-Induced Psoriasis in Mice.

There is compelling evidence that CD4+Foxp3+ regulatory T cells (Tregs) are indispensable in the inhibition of autoimmune inflammatory responses, including psoriasis. Recently, we showed that systemically treatment with tetrandrine (TET), a two-pore channel inhibitor identified from the Chinese herb Stephania tetrandra S. Moor, could promote the proliferative expansion of Tregs in mice through stimulation of TNF-TNFR2 interaction. We thus hypothesized that topical administration of TET might also expand Tregs and consequently inhibit psoriasis. To this end, we developed a TET nanoemulsion and examined its effect on the expansion of Tregs after topical administration on mouse psoriasis induced by imiquimod. The result of our experiment showed that topical treatment with TET nanoemulsion markedly increased the proportion and number of Tregs in the spleen, as well as TNFR2 and Ki-67 expression by Tregs, in WT and TNFR1 KO mice, but not in TNFR2 KO mice. Consequently, TET nanoemulsion potently inhibited IL-17-expressing cells in the spleen and lymph nodes of imiquimod-treated WT mice, accompanied by decreased serum levels of IL-17A, INF-γ, and TNF and their mRNA levels in the flamed lesion. Importantly, TET nanoemulsion treatment markedly inhibited the development of psoriasis-like disease in WT and TNFR1 KO mice but not in TNFR2 KO mice. Therefore, our study indicates that the topical administration of TET could also stimulate the expansion of Tregs through the TNF-TNFR2 pathway. This effect of TET and its analogs may be useful in the treatment of inflammatory skin diseases such as psoriasis.

Effects of different concentrations of human umbilical cord mesenchymal stem cells to ameliorate psoriasis-like skin lesions in BALB/c mice.

BackgroundPsoriasis is an immune-mediated chronic, recurrent, inflammatory skin disease. In view of the research on the relationship between stem cells and the pathogenesis of psoriasis, stem cells may be a new breakthrough in the systemic treatment of psoriasis.MethodsThe BALB/c mouse psoriasis-like model induced by imiquimod was established and animals were randomly divided into a control group, model group, human umbilical cord mesenchymal stem cells (hUC-MSCs) group with different concentrations (injected separately with umbilical cord stem cells 1×107/kg, 2×107/kg, 4×107/kg through the caudal vein) and fresh hUC-MSCs group (injected with fresh umbilical cord stem cells 2×107/kg through the tail vein). The Psoriasis Area and Severity Index (PASI) score was used to observe the changes in skin lesions. The epidermal thickness, degree of keratinization and infiltration of inflammatory cells were observed by HE staining. The concentrations of TNF-α, IFN-γ, IL-17A, IL-23 and other cytokines in serum and skin of mice were measured by enzyme-linked immunosorbent assay (ELISA).ResultsMice treated with hUC-MSCs showed a good dose-response dependence compared with the control group. As the concentration of hUC-MSCs increased, so did the spleen index. According to the PASI integral trend chart, hUC-MSCs can delay the appearance of skin lesions and accelerate the recovery of skin lesions. HE staining showed that the number of parakeratosis cells in the hUC-MSCs treatment group was significantly decreased, and the degree of dermal hyperplasia and inflammatory cell infiltration in erythrocyte extravasation was significantly lower than in the model group. The higher the concentration of hUC-MSCs, the lower the concentration of the four cytokines in serum and skin tissue.ConclusionshUC-MSCs had an obvious therapeutic effect on imiquimod-induced psoriasis in mice, and a high concentration of hUC-MSCs had the best therapeutic effect. This effect intensity is dose-dependent, and hUC-MSCs at high concentrations have better therapeutic effect.

Gut and Cutaneous Microbiome Featuring Abundance of Lactobacillus reuteri Protected Against Psoriasis-Like Inflammation in Mice.

BackgroundPsoriasis is a chronic autoinflammatory skin disease, and its aetiology remains incompletely understood. Recently, gut microbial dysbiosis is found to be tightly associated with psoriasis.ObjectiveWe sought to reveal the causal role of gut microbiota dysbiosis in psoriasis pathogenesis and investigate the protective effect of healthy commensal bacteria against imiquimod -induced psoriasis-like skin response.MethodsBy using fecal microbial transplantation (FMT), 16S rRNA gene-based taxonomic profiling and Lactobacillus supplement, we have assessed the effect of FMT from healthy individuals on psoriasis-like skin inflammation and associated immune disorders in imiquimod-induced psoriasis mice.ResultsHere, by using psoriasis mice humanized with the stools from healthy donors and psoriasis patients, the imiquimod-induced psoriasis in mice with psoriasis patient stool was found to be significantly aggravated as compared to the mice with healthy donor stools. Further analysis showed fecal microbiota of healthy individuals protected against Treg/Th17 imbalance in psoriasis. Moreover, we found the gut and skin microbiome in mice receipted with gut microbiota of healthy individuals (HD) differed from those of mice receipted with gut microbiota of psoriasis patients (PSD). 16S rRNA sequencing revealed that Lactobacillus reuteri was greatly enriched in fecal and cutaneous microbiome of HD mice as compared to PSD mice. Intriguingly, supplement with Lactobacillus reuteri was sufficient to increase the expression of anti-inflammatory gene IL-10, reduce Th17 cells counts and confer resistance to imiquimod-induced inflammation on the mice with gut microbiota dysbiosis.ConclusionOur results suggested that the gut microbiota dysbiosis is the potential causal factor for psoriasis and the gut microbiota may serve as promising therapy target for psoriasis patients.