Anti-Angiogenic Efficacy of PSORI-CM02 and the Associated Mechanism in Psoriasis In Vitro and In Vivo.

Psoriasis is a chronic proliferative autoimmune dermatologic disease characterised by abnormal angiogenesis. Thus, regulating angiogenesis in the skin is an important treatment strategy for psoriasis. PSORI-CM02, an empirical Chinese medicine formula optimised from Yin Xie Ling, was created by the Chinese medicine specialist, Guo-Wei Xuan. Clinical studies have shown that PSORI-CM02 is safe and effective for the treatment of psoriasis. However, its anti-psoriatic mechanisms remain to be further explored. In this study, we investigated the effects of PSORI-CM02 on angiogenesis in the skin and the underlying mechanisms in IL-17A-stimulated human umbilical vein endothelial cells (HUVECs) and a murine model of imiquimod (IMQ)-induced psoriasis. In vitro, PSORI-CM02 significantly inhibited the proliferation and migration of IL-17A-stimulated HUVECs in a dose-dependent manner. Further, it markedly regulated the antioxidative/oxidative status and inflammation; suppressed the expression of VEGF, VEGFR1, VEGFR2, ANG1, and HIF-1α; and reduced the phosphorylation of MAPK signalling pathway components in IL-17A-stimulated HUVECs. In vivo studies showed that PSORI-CM02 markedly reduced angiogenesis in the skin of mice with IMQ-induced psoriasis, while significantly rebalancing antioxidant/oxidant levels; inhibiting the production of IL-6, TNF-α, IL-17A, and IL-17F; and repressing the synthesis of angiogenic mediators. In addition, PSORI-CM02 markedly reduced the activation of the MAPK signalling pathway in psoriatic skin tissue. Taken together, our results demonstrated that PSORI-CM02 inhibited psoriatic angiogenesis by reducing the oxidative status and inflammation, suppressing the expression of angiogenesis-related molecules, and inhibiting the activation of the MAPK signalling pathway in vitro and in vivo.

Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles ameliorate collagen-induced arthritis via immunomodulatory T lymphocytes.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease for which there are currently no effective therapies. Although mesenchymal stem cells (MSCs) can prevent arthritis through immunomodulatory mechanisms, there are several associated risks. Alternatively, MSC-derived small extracellular vesicles (sEVs) can mimic the effects of MSCs, while reducing the risk of adverse events. However, few studies have examined sEVs in the context of RA. Here, we evaluate the immunomodulatory effects of human umbilical cord MSC (hUCMSC)-derived sEVs on T lymphocytes in a collagen-induced arthritis (CIA) rat model to elucidate the possible mechanism of sEVs in RA treatment. We then compare these mechanisms to those of MSCs and methotrexate (MTX). METHODS: The arthritis index and synovial pathology were assessed. T lymphocyte proliferation and apoptosis, Th17 and Treg proportions, and interleukin (IL)-17, IL-10, and transforming growth factor (TGF)-ß expression were detected using flow cytometry. Retinoic acid receptor-related orphan receptor gamma t (RORγt) and forkhead box P3 (FOXP3), which are master transcriptional regulators of Th17 and Treg differentiation, were also assessed using immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: sEV treatment ameliorated arthritis and inhibited synovial hyperplasia in a dose-dependent manner. These effects were mediated by inhibiting T lymphocyte proliferation and promoting their apoptosis, while decreasing Th17 cell proportion and increasing that of Treg cells in the spleen, resulting in decreased serum IL-17, and enhanced IL-10 and TGF-ß expression. Transcriptionally, sEVs decreased RORγt and increased FOXP3 expression in the spleen, and decreased RORγt and FOXP3 expression in the joints. In some aspects sEVs were more effective than MSCs and MTX in treating CIA. CONCLUSIONS: hUCMSC-derived sEVs ameliorate CIA via immunomodulatory T lymphocytes, and might serve as a new therapy for RA.

Cryptotympana pustulata Extract and Its Main Active Component, Oleic Acid, Inhibit Ovalbumin-Induced Allergic Airway Inflammation through Inhibition of Th2/GATA-3 and Interleukin-17/RORγt Signaling Pathways in Asthmatic Mice.

Cicadae Periostracum (CP), derived from the slough of Cryptotympana pustulata, has been used as traditional medicine in Korea and China because of its diaphoretic, antipyretic, anti-inflammatory, antioxidant, and antianaphylactic activities. The major bioactive compounds include oleic acid (OA), palmitic acid, and linoleic acid. However, the precise therapeutic mechanisms underlying its action in asthma remain unclear. The objective of this study was to determine the antiasthmatic effects of CP in an ovalbumin (OVA)-induced asthmatic mouse model. CP and OA inhibited the inflammatory cell infiltration, airway hyperresponsiveness (AHR), and production of interleukin (IL)7 and Th2 cytokines (IL-5) in the bronchoalveolar lavage fluid and OVA-specific imunoglobin E (IgE) in the serum. The gene expression of IL-5, IL-13, CCR3, MUC5AC, and COX-2 was attenuated in lung tissues. CP and OA might inhibit the nuclear translocation of GATA-binding protein 3 (GATA-3) and retinoic acid receptor-related orphan receptor γt (RORγt) via the upregulation of forkhead box p3 (Foxp3), thereby preventing the activation of GATA-3 and RORγt. In the in vitro experiment, a similar result was observed for Th2 and GATA-3. These results suggest that CP has the potential for the treatment of asthma via the inhibition of the GATA-3/Th2 and IL-17/RORγt signaling pathways.

Ingredients such as trehalose and hesperidin taken as supplements or foods reverse alterations in human T cells, reducing asbestos exposure-induced antitumor immunity.

Exposure of human immune cells to asbestos causes a reduction in antitumor immunity. The present study aimed to investigate the recovery of reduced antitumor immunity by several ingredients taken as supplements or foods, including trehalose (Treh) and glycosylated hesperidin (gHesp). Peripheral blood CD4+ cells were stimulated with IL­2, anti­CD3 and anti­CD28 antibodies for 3 days, followed by further stimulation with IL­2 for 7 days. Subsequently, cells were stimulated with IL­2 for an additional 28 days. During the 28 days, cells were cultured in the absence or presence of 50 µg/ml chrysotile asbestos fibers. In addition, cells were treated with 10 mM Treh or 10 µM gHesp. Following culture for 28 days, reverse transcription­quantitative PCR was performed to assess the expression levels of transcription factors, cytokines and specific genes, including matrix metalloproteinase­7 (MMP­7), nicotinamide nucleotide transhydrogenase (NNT) and C­X­C motif chemokine receptor 3, in unstimulated cells (fresh) and cells stimulated with PMA and ionomycin (stimuli). The results demonstrated that compared with the control group, chrysotile­exposure induced alterations in MMP­7, NNT and IL­17A expression levels were not observed in the 'Treh' and 'gHesp' groups in stimulated cells. The results suggested that Treh and gHesp may reverse asbestos exposure­induced reduced antitumor immunity in T helper cells. However, further investigation is required to confirm the efficacy of future trials involving the use of these compounds with high­risk human populations exposed to asbestos, such as workers involved in asbestos­handling activities.

Chitosan Oligosaccharides Suppress Nuclear Factor-Kappa B Activation and Ameliorate Experimental Autoimmune Uveoretinitis in Mice.

We investigated the therapeutic potential and mechanism of chitosan oligosaccharides (COS) for experimental autoimmune uveoretinitis (EAU) in mice. EAU was induced in C57/BL6 mice by injection of human interphotoreceptor retinoid-binding protein (IRBP) peptides. At the same time, a high or low dose (20 or 10 mg/kg) of COS or phosphate-buffered saline (PBS) was given to mice daily after EAU induction. We found that mouse EAU is ameliorated by the high-dose COS treatment when compared with PBS treatment. In the retinas of high-dose COS-treated mice, the nuclear translocation of NF-κB subunit (p65) was suppressed, and the expression of several key EAU inflammatory mediators, IFN-γ, TNF-α, IL-1α, IL-4, IL-5, IL-6, IL-10, IL-17 and MCP-1 was lowered. These results suggest that COS may be a potential treatment for posterior uveitis.

Electroacupuncture with Bushen Jiannao improves cognitive deficits in senescence-accelerated mouse prone 8 mice by inhibiting neuroinflammation.

OBJECTIVE: To investigate effect of electroacupuncture (EA) with Bushen Jiannao on learning and memory ability in senescence-accelerated mouse prone 8 (SAMP8) mice and the related mechanisms. METHODS: 8-month-old senescence-accelerated-resistant (SAMR1) and SAMP8 mice were treated with EA at Baihui (GV 20), Shenshu (BL 23), and Taixi (KI 3) acupoint once a week for 8 weeks. The Morris water maze, enzyme linked immunosorbent assay, immunohistochemistry, and Western blot were used to assess Alzheimer's disease (AD)-associated cognitive and neuroinflammatory phenotypes. RESULTS: Our data showed that EA treatment decreased activation of microglia and astrocytes, decreased levels of inflammatory factors including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-17, and improved spatial memory deficits in SAMP8 mice. EA therapy with Bushen Jiannao exhibited anti-inflammatory properties and improved cognitive function. CONCLUSION: The present study indicates that EA treatment based on the interaction between kidney and brain can improve learning and memory ability by inhibiting activation of astrocytes and microglia and decreasing expression of pro-inflammatory cytokines, TNF-α and IL-17. EA treatment based on the interaction between kidney and brain may be an effective treatment for AD.

Effectiveness of Xiaoyin Jiedu granules in the treatment of psoriasis vulgaris in patients with blood-heat symptom patterns in terms of Traditional Chinese Medicine.

OBJECTIVE: To evaluate the effectiveness of Xiaoyin Jiedu (XYJD) granules in the treatment of psoriasis vulgaris (PSV) in patients with a blood-heat pattern (BHP) in terms of Traditional Chinese Medicine (TCM). We also aimed to identify the possible underlying immunological mechanism. METHODS: Twenty-five PSV patients with BHP and ten normal controls were enrolled from January 1, 2015 to December 31, 2016. Patients were randomly assigned to either the XYJD group (15 cases) or the placebo group (10 cases), in which patients were treated with XYJD granules or a placebo, respectively. Additionally, albolene was used to relieve skin dryness in these two groups. The psoriasis area and severity indexes, dermatology life quality indexes and itching scores were assessed at the end of the 2nd, 4th and 8th week of treatment. The number of peripheral blood T helper (Th) 9, Th17 and regulatory T cells (Tregs) and the mRNA and protein expression levels of PU.1, RAR-related orphan receptor (ROR)-γt, forkhead box protein 3 (Foxp3), interleukin (IL)-9, IL-17, IL-23 and IL-10 in the control and experimental groups were compared before and after treatment. RESULTS: Psoriasis area and severity indexes and itching scores of patients in the XYJD group were significantly lower than those in the placebo group, whereas dermatology life quality indexes were significantly higher. In comparison with the placebo group, XYJD granules significantly reduced the number of Th17 cells and the mRNA and protein expression levels of Th17-related ROR-γt, IL-17, IL-22 and IL-23 in the peripheral blood and reduced the number of Th9 cells and the mRNA and protein expression levels of Th9-related PU.1 and IL-9. CONCLUSION: XYJD granules were effective against PSV in patients with BHP by reducing the number of Th9 and Th17 cells and the levels of their related cytokines.

Status of a real-life cohort of patients with moderate-to-severe plaque psoriasis treated with secukinumab and considerations on the use of biological agents in the Covid-19 era.

INTRODUCTION: In light of the current Covid-19 pandemic and the ongoing, extensive debate about the use of biological agents in psoriatic patients, we felt compelled to relate our experience in the use of secukinumab in the same cohort before and during the lockdown in Italy. Areas covered: Secukinumab was not discontinued, and there were no cases of confirmed infection with SARS-CoV-2 in this cohort. Expert opinion: In our practice, there is no evidence favoring the discontinuation of secukinumab in these patients. We also present a brief commentary on the use of biological agents in patients with moderate-to-severe plaque psoriasis.

Mechanism of berberine in treating Helicobacter pylori induced chronic atrophic gastritis through IRF8-IFN-γ signaling axis suppressing.

AIMS: In this study, we will investigate the therapeutic effects of berberine (BBR) in Helicobacter pylori (H. pylori) induced chronic atrophic gastritis (CAG). Furthermore, potential mechanisms of BBR in regulating IRF8-IFN-γ signaling axis will also be investigated. MATERIALS AND METHODS: H. pylori were utilized to establish CAG model of rats. Therapeutic effects of BBR on serum supernatant indices, and histopathology of stomach were analyzed in vivo. Moreover, GES-1 cells were infected by H. pylori, and intervened with BBR in vitro. Cell viability, morphology, proliferation, and quantitative analysis were detected by high-content screening (HCS) imaging assay. To further investigate the potential mechanisms of BBR, relative mRNA, immunohistochemistry and protein expression in IRF8-IFN-γ signaling axis were measured. KEY FINDINGS: Results showed serum supernatant indices including IL-17, CXCL1, and CXCL9 were downregulated by BBR intervention, while, G-17 increased significantly. Histological injuries of gastric mucosa induced by H. pylori also were alleviated. Moreover, cell viability and morphology changes of GES-1 cells were improved by BBR intervention. In addition, proinflammatory genes and IRF8-IFN-γ signaling axis related genes, including Ifit3, Upp1, USP18, Nlrc5, were suppressed by BBR administration in vitro and in vivo. The proteins expression related to IRF8-IFN-γ signaling axis, including Ifit3, IRF1 and Ifit1 were downregulated by BBR intervention.

Biologic therapies for the treatment of hidradenitis suppurativa.

Introduction: Hidradenitis suppurativa (HS) is a chronic skin disorder characterized by inflammatory nodules, abscesses, and fistulae. Patients tend to present in young adulthood and are predominantly female. The pathogenesis of HS involves apopilosebaceous gland follicle occlusion and affected areas often occur where this type of gland predominates. Treatment selection depends on HS severity, which is included in different scoring systems. In recent years, biological therapies have been evaluated and used with increasing frequency in moderate-to-severe HS disease.Areas covered: This review focuses on biological therapies for HS as assessed in case reports, case series, and clinical trials. The efficacy, hidradenitis suppurativa scoring systems, and long-term results of these therapies are discussed depending on the studies' endpoints.Expert opinion: Adalimumab is currently the only FDA-approved HS biological therapy. Some patients do not experience treatment efficacy with adalimumab at 40 mg/week, which may result in increasing the dose or seeking other treatments. Infliximab is the next line of HS treatment with demonstrated efficacy. Other biological therapies being studied have demonstrated efficacy in small patient groups, but lack study power. Further studies may provide answers to seeking treatment options for patients who fail to improve on current standard HS treatment.

Efficacy of Shenqi Pollen Capsules for High-Altitude Deacclimatization Syndrome via Suppression of the Reoxygenation Injury and Inflammatory Response.

High-altitude deacclimatization syndrome (HADAS) is involved in hypoxia-reoxygenation injury and inflammatory response, induced a series of symptoms, and has emerged as a severe public health issue. Here, we investigated the mechanism as well as potential means to prevent HADAS using Shenqi pollen capsules (SPCs) in subjects with HADAS in a multicenter, double-blinded, randomized, placebo-controlled study. All subjects were at the same high altitude (3650 m) for 4-8 months before returning to lower altitudes. Subjects (n = 288) in 20 clusters were diagnosed with mild or moderate HADAS on the third day of the study. We randomly allocated 20 clusters of subjects (1 : 1) to receive SPCs or a placebo for 7 weeks, and they were then followed up to the 14th week. The primary endpoints were subjects' HADAS scores recorded during the 14 weeks of follow-up. Compared with the placebo, SPC treatment significantly decreased the subjects' HADAS scores and reduced the incidence of symptom persistence. SPC therapy also reduced the serum levels of CK, CK-MB, LDH, IL-17A, TNF-α, and miR-155 and elevated IL-10 and miR-21 levels. We thus demonstrate that SPCs effectively ameliorated HADAS symptoms in these subjects via suppression of the hypoxia-reoxygenation injury and inflammatory response.

Predictive role of IL-17A/IL-10 ratio in persistent asthmatic patients on vitamin D supplement.

Asthma is an airway inflammatory disorder. Vitamin (Vit) D is a potent immuno-modulator. It suppresses Interleukin (IL)-17 and induces IL-10. This study aims to investigate the role of IL-17A and IL-10 in predicting asthma control in case of Vit D supplementation. Seventy-nine patients enrolled in this study (42 patients received Vit D supplement and 37 patients did not receive the supplement). The enrolled patients were assessed at the beginning of this study and after 3 months. At the end of the study, there was a significant improvement in pulmonary function parameters in the Vit D supplemented group when compared to both the baseline values and the non-supplemented group. There was a significant decrease in serum IL-17A levels and a significant increase in serum IL-10 levels in comparison with the baseline values (p < 0.0001). The highest correlation of FEV1% improvement percentage was associated with the baseline IL-17A/IL-10 ratio (r = 0.65; p < 0.0001). The IL-17A/IL-10 ratio at a cutoff ≥ 2.66 had a sensitivity of 72.2% and a specificity of 83.3%. The IL-17A/IL-10 ratio had an adjusted odds ratio = 4.66 (p = 0.04). Vit D supplementation reduces the serum IL-17A levels and elevates the serum IL-10 levels in persistent asthmatic patients. So, Vitamin D can be used as an adjunct therapy side by side with the conventional asthma therapy. The IL-17A/IL-10 ratio seems to be a possible predictive biomarker for asthma improvement in patients depending on Vit D supplementation.

Antagonistic effect of vitamin E on nAl2O3-induced exacerbation of Th2 and Th17-mediated allergic asthma via oxidative stress.

Some basic research has shown that nanomaterials can aggravate allergic asthma. However, its potential mechanism is insufficient. Based on the research that alumina nanopowder (nAl2O3) has been reported to cause lung tissue damage, the purpose of this study was to explore the relationship between nAl2O3 and allergic asthma as well as its molecular mechanism. In this study, Balb/c mice were sensitized with ovalbumin (OVA) to construct the allergic asthma model while intratracheally administered 0.5, 5 or 50 mg kg-1·day-1 nAl2O3 for 3 weeks. It was observed that exposure to nAl2O3 exacerbated airway hyperresponsiveness (AHR), airway remodeling, and inflammation cell infiltration, leading to lung function damage in mice. Results revealed that nAl2O3 could increase ROS levels and decrease GSH levels in lung tissue, promote the increases of the T-IgE, TGF-ß, IL-1ß and IL-6 levels, stimulate the overexpression of transcription factors GATA-3 and RORγt, decrease the levels of IFN-γ and IL-10 and increase the levels of IL-4 and IL-17A, resulting in the imbalance of Th1/Th2 and Treg/Th17 immune responses. In addition, antioxidant Vitamin E (Vit E) could alleviate asthma-like symptoms through blocking oxidative stress. The study displayed that exposure of nAl2O3 deteriorated allergic asthma through promoting the imbalances of Th1/Th2 and Treg/Th17.

Are new variants of psoriasis therapy (IL-17 inhibitors) safe?

Psoriasis is a chronic, recurrent, inflammatory, and proliferative skin disease. Its etiology has not yet been fully assessed, but undoubtedly it is a multifaceted disease. The key role in its pathomechanism is played by genetic, immunologic, and environmental factors and stress. If traditional methods of psoriasis treatment (phototherapy, methotrexate, retinoids, cyclosporine A) fail, we reach for the following biopharmaceuticals - infliximab, etanercept, adalimumab, or ustekinumab. However, genetic engineering progress discovers new possibilities - the pending clinical trials involve IL-17, IL-23 antagonists, PDE4 and -3 and -1. Psoriasis etiopathogenesis mainly involves the IL-17A, IL-17F, and IL-17A/F subtypes, which affect the keratinocytes. The biological therapy molecularly oriented with the antagonists of interleukin 17 is based mainly on the influence onto the cytokine in the manner that prevents it from binding with the receptor. Three biopharmaceuticals are currently under third phase studies: two fully humanized antibodies neutralizing IL-17 - ixekizumab and secukinumab, and one human monoclonal antibody, brodalumab. The below work will be devoted to the analysis of possible undesirable symptoms, which were observed during the studies. We will try to review the latest literature concerning the most important clinical trials conducted in many centers.

Current understanding of the role of dietary lipids in the pathophysiology of psoriasis.

Dietary lipids are fundamental nutrients for human health. They are typically composed of various long-chain fatty acids which include saturated fatty acids (SFAs) and unsaturated fatty acids (UFAs). UFAs are further classified into several groups, such as omega-3 polyunsaturated fatty acids (PUFAs) and omega-6 PUFAs, depending on their chemical structure. Epidemiological studies have suggested the involvement of dietary lipids in the progression or regulation of psoriasis, a common chronic inflammatory skin disease induced via the IL-23/IL-17 axis. Although the underlying mechanisms by which dietary lipids regulate psoriasis have remained unclear, with the advancement of experimental techniques and the development of psoriasis mouse models, various possible mechanisms have been proposed. For example, SFAs may facilitate psoriatic dermatitis by causing activation of the inflammasome in keratinocytes and macrophages or by inducing IL-17-producing cells, such as Th17 and IL-17-producing γδ T cells in the skin, while omega-3 PUFAs may play inhibitory roles by suppressing Th17 differentiation. In this review, we summarize current data on the roles of dietary lipids in the development of psoriasis as revealed by mouse studies, and we discuss potential therapeutic strategies for psoriasis from the perspective of dietary lipids.

Epigallocatechin gallate ameliorates airway inflammation by regulating Treg/Th17 imbalance in an asthmatic mouse model.

Epigallocatechin gallate (EGCG) is a polyphenol that is found in green tea that has been shown to ameliorate airway inflammation in an ovalbumin-sensitized asthmatic mouse model. The purpose of this study was to investigate whether the immunomodulatory and anti-inflammatory effects of EGCG by regulating the regulatory T cell (Treg)/Th 17 cells balance in this model. Female BALB/c mice were sensitized and challenged with ovalbumin by intraperitoneal injection. EGCG was administered to asthmatic mice intraperitoneally 1 h before each OVA challenge. Airway hyperresponsiveness (AHR) was measured, and lung inflammatory infiltrations were assessed by hematoxylin and eosin (HE) staining. Serum OVA-specific IgE levels, Interleukin-10 (IL-10) levels and Interleukin-17A (IL-17A) levels in the bronchoalveolar lavage fluid (BALF), serum, and splenocyte culture supernatants were measured by ELISA. Flow cytometry was used to assess the effects of EGCG on the frequency of CD4+CD25+Foxp3+Treg cells in the splenocytes and real-time PCR method was used to measure the expression of Forkhead box P3 (Foxp3) mRNA and retinoid-related orphan receptor gammat (RORγt) mRNA in the lung tissue. The results showed that administration of EGCG significantly decreased AHR and OVA specific IgE in the serum, increased IL-10 levels in the BALF, serum, and splenocyte culture supernatant, and the frequency of CD4+CD25+Foxp3+Treg cells in the splenocytes in asthmatic mice. Administration of EGCG also ameliorated airway inflammation and eosinophil infiltrations in asthmatic mice. These results suggested that EGCG likely ameliorated OVA-induced airway inflammation by increasing the production of IL-10, the number of CD4+CD25+Foxp3+Treg cells and expression of Foxp3 mRNA in the lung tissue, and it could be an effective agent for treating asthma.

Retinoic acid-induced autoantigen-specific type 1 regulatory T cells suppress autoimmunity.

Regulatory T (Treg) cells help to maintain tolerance and prevent the development of autoimmune diseases. Retinoic acid (RA) can promote peripheral conversion of naïve T cells into Foxp3+ Treg cells. Here, we show that RA can act as an adjuvant to induce antigen-specific type 1 Treg (Tr1) cells, which is augmented by co-administration of IL-2. Immunization of mice with the model antigen KLH in the presence of RA and IL-2 induces T cells that secrete IL-10, but not IL-17 or IFN-γ, and express LAG-3, CD49b and PD-1 but not Foxp3, a phenotype typical of Tr1 cells. Furthermore, immunization of mice with the autoantigen MOG in the presence of RA and IL-2 induces Tr1 cells, which suppress pathogenic Th1 and Th17 cells that mediate the development of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease of the CNS. Furthermore, immunization with a surrogate autoantigen, RA and IL-2 prevents development of spontaneous autoimmune uveitis. Our findings demonstrate that the induction of autoantigen-specific Tr1 cells can prevent the development of autoimmunity.

A novel RORγt inhibitor is a potential therapeutic agent for the topical treatment of psoriasis with low risk of thymic aberrations.

BACKGROUND: Retinoic acid receptor-related orphan receptor gamma t (RORγt) has critical roles in the development, maintenance and function of interleukin (IL)-17-producing cells and is a highly attractive target for the treatment of IL-17-mediated autoimmune disease, particularly psoriasis. On the other hand, RORγt is also critical for controlling apoptosis during thymopoiesis, and genetic RORγt ablation or systematic RORγt inhibition cause progressive thymic aberrations leading to T cell lymphomas. OBJECTIVE: We investigated whether topical administration of our novel RORγt inhibitor, S18-000003 has therapeutic potential for psoriasis with low risk of thymic aberrations. METHODS: We evaluated the effect of topical S18-000003 on psoriasis-like skin inflammation and influence on the thymus in a 12-O-tetradecanoylphorbol-13-acetate-induced K14.Stat3C mouse psoriasis model. RESULTS: S18-000003 markedly inhibited the development of psoriatic skin inflammation via suppression of the IL-17 pathway. In the skin, S18-000003 suppressed all subsets of IL-17-producing cells that we previously identified in this psoriasis model: Th17 cells, Tc17 cells, dermal γδ T cells, TCR- cells that probably included innate lymphoid cells, and CD4-CD8- double-negative αß T cells. Notably, neither reduction of CD4+CD8+ double-positive thymocytes nor dysregulation of cell cycling was observed in S18-000003-treated mice, even at a high dose. CONCLUSION: Our topically administered RORγt inhibitor is a potential therapeutic agent for psoriasis with low risk of thymic lymphoma.

Hyperglycemia Is Associated with Psoriatic Inflammation in Both Humans and Mice.

Chronic low-grade inflammation can cause several metabolic syndromes. Patients with psoriasis, a chronic immunological skin inflammation, often develop diabetes. However, it is not clear to date how psoriasis leads to, or is correlated with, glucose intolerance. Here, we investigate whether psoriasis itself is correlated with hyperglycemia in humans and mice. In patients, the severity of psoriasis was correlated with high blood glucose levels, and treatment of psoriasis by phototherapy improved insulin secretion. Imiquimod-induced systemic and cutaneous inflammation in mice, with features of human psoriasis, also resulted in hyperglycemia. Although it should be determined if psoriasis-like cutaneous inflammation alone can induce hyperglycemia, imiquimod-treated mice showed impairment of insulin secretion without significant islet inflammation. Administration of anti-IL-17A monoclonal antibody improved hyperglycemia in patients with psoriasis and imiquimod-treated mice with psoriasiform features. These results suggest that hyperglycemia is highly associated with psoriasis, mainly through IL-17.

Total Glycosides of Peony Protects Against Inflammatory Bowel Disease by Regulating IL-23/IL-17 Axis and Th17/Treg Balance.

Inflammatory bowel disease (IBD) is a group of autoimmune diseases, including ulcerative colitis and Crohn's disease, characterized by nonspecific inflammation in the gut. Total glycoside of peony (TGP) has been widely used for treatment of autoimmune diseases because of its pharmacological effects. However, it is lack of depth in whether TGP regulate T helper 17 cell (Th17) / T regulatory cell (Treg) immune balance or interleukin 23 (IL-23) / IL-17 axis to achieve the goal of treating IBD. Hence, the aim of this study was to investigate the effects of TGP on experimental colitis mice and the related mechanisms. In the present study, we demonstrated that administration of TGP effectively attenuates colonic inflammation of TNBS-induced colitis mice, mainly reflected in significantly improved clinical parameters, reduced inflammatory response and myeloperoxidase (MPO) activity, even stronger systemic immune ability and effective improvement of Th17/Treg immune disorders. In addition, there was a stronger immunosuppressive ability in a positive cluster of differentiation 4 (CD4 + ) T-lymphocytes from the TGP treated mouse colon, characterized by the inhibition of high levels of inflammatory factors and increased regulatory T cells. Importantly, high-dose TGP has similar therapeutic effects as salicylazosulfapyridine (SASP) on IBD treatment. The potential mechanisms might be, at least in part, related to the adjustment of imbalance of Th17/Treg cells and the inhibition of IL-23/IL17 inflammatory signal axis.