Dataset Information

PSORI-CM02 Formula Increases CD4+ Foxp3+ Regulatory T Cell Frequency and Ameliorates Imiquimod-Induced Psoriasis in Mice.

ABSTRACT: Psoriasis is an autoimmune and inflammatory disease, which is estimated to affect 2-3% of the population in the world. PSORI-CM02 is an empirical formula of Chinese medicine optimized from Yin Xie Ling, which is widely used to treat psoriasis in China for decades. However, its antipsoriatic mechanisms are still not well understood. Here, we explored the therapeutic effects of PSORI-CM02 on psoriasis and its mechanisms of action in imiquimod-induced psoriasis-like mouse models and human HaCaT cells. In experiments in vitro, PSORI-CM02 significantly inhibited HaCaT cell proliferation in dose-dependent and time-dependent manners. Furthermore, it hindered the progression of HaCaT cell cycle and arrested HaCaT cells at G1 phase. On the other hand, our in vivo studies demonstrated that PSORI-CM02 dramatically reduced psoriasis area and severity index scores and lesion temperature in imiquimod-induced psoriatic mice. The antioxidative activities of glutathione, catalase, and superoxide dismutase were increased while oxidative activity of malonaldehyde was markedly decreased after treatments with PSORI-CM02. PSORI-CM02 also suppressed the mRNA expression of proinflammatory cytokines, including TNF-?, IL-6, and IL-17, and lowered their protein levels in the serum as well. In addition, PSORI-CM02 could reduce the expression of IKK? and NF-?B in psoriatic skin tissue. It also upregulated the proportion of CD4+ Foxp3+ regulatory T cells (Tregs) in both lymph nodes and spleens and promoted CD4+ CD25+ Treg proliferation in vitro. Taken together, our research demonstrated that PSORI-CM02 inhibited HaCaT cell proliferation by arresting them at G1 phase and alleviated systemic inflammation and psoriasis in mice via altering the oxidative/anti-oxidative status, tipping the balance between Th17 responsiveness and CD4+ Foxp3+ Treg generation, and suppressing the expression of proinflammatory cytokines as well as NF-?B signaling.

SUBMITTER: Chen H

PROVIDER: S-EPMC5766646 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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PSORI-CM02 Formula Increases CD4+ Foxp3+ Regulatory T Cell Frequency and Ameliorates Imiquimod-Induced Psoriasis in Mice.

Chen Haiming H Liu Huazhen H Lu Chuanjian C Wang Maojie M Li Xiong X Zhao Hui H Yan Yuhong Y Yu Wanling W Han Ling L Dai Zhenhua Z

Frontiers in immunology 20180108

Psoriasis is an autoimmune and inflammatory disease, which is estimated to affect 2-3% of the population in the world. PSORI-CM02 is an empirical formula of Chinese medicine optimized from Yin Xie Ling, which is widely used to treat psoriasis in China for decades. However, its antipsoriatic mechanisms are still not well understood. Here, we explored the therapeutic effects of PSORI-CM02 on psoriasis and its mechanisms of action in imiquimod-induced psoriasis-like mouse models and human HaCaT cel ...[more]

PMID: 29358932

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Project description:Psoriasis is an autoimmune and inflammatory skin disease affecting around 2-3% of the world's population. Patients with psoriasis need extensive treatments with global immunosuppressive agents that may cause severe side effects. Esculetin, a type of coumarins, is an active ingredient extracted mainly from the bark of Fraxinus rhynchophylla, which has been used to treat inflammatory and autoimmune diseases in China. However, the antipsoriatic effects of esculetin have not been reported. In this study, we aimed to investigate the effects of esculetin on psoriatic skin inflammation in a mouse model and explored the potential molecular mechanisms underlying its action. We found that esculetin ameliorated the skin lesion and reduced PASI scores as well as weight loss in imiquimod-induced psoriasis-like mice, accompanied with weakened proliferation and differentiation of keratinocytes and T cell infiltration in esculetin-treated psoriatic mice. In addition, esculetin reduced the frequency of CD8+CD44highCD62Llow effector T cells in psoriatic mice. In contrast, it increased the frequency of CD4+Foxp3+ Tregs in both lymph nodes and spleens of the psoriatic mice while promoting the differentiation of CD4+CD25- T cells into CD4+Foxp3+ Tregs in vitro. Interestingly, depleting CD4+Foxp3+ Tregs largely reversed esculetin-mediated reduction in PASI scores, indicating that esculetin attenuates murine psoriasis mainly by inducing CD4+Foxp3+ Tregs. Furthermore, the mRNA levels of proinflammatory cytokines in the psoriatic mouse skin, including IL-6, IL-17A, IL-22, IL-23, TNF-α, and IFN-γ, were dramatically decreased by the treatment with esculetin. Finally, we found that esculetin inhibited the phosphorylation of IKKα and P65 in the psoriatic skin, suggesting that it inhibits the activation of NF-κB signaling. Thus, we have demonstrated that esculetin attenuates psoriasis-like skin lesion in mice and may be a potential therapeutic candidate for the treatment of psoriasis in clinic.

Project description:BackgroundThe polyphenol resveratrol has anti-inflammatory effects in various cells, tissues, animals and human settings of low-grade inflammation. Psoriasis is a disease of both localized and systemic low-grade inflammation. The Sirtuin1 enzyme thought to mediate the effects of resveratrol is present in skin and resveratrol is known to down regulate NF-κB; an important contributor in the development of psoriasis. Consequently we investigated whether resveratrol has an effect on an Imiquimod induced psoriasis-like skin inflammation in mice and sought to identify candidate genes, pathways and interleukins mediating the effects.MethodsThe study consisted of three treatment groups: A control group, an Imiquimod group and an Imiquimod+resveratrol group. Psoriasis severity was assessed using elements of the Psoriasis Area Severity Index, skin thickness measurements, and histological examination. We performed an RNA microarray from lesional skin and afterwards Ingenuity pathway analysis to identify affected signalling pathways. Our microarray was compared to a previously deposited microarray to determine if gene changes were psoriasis-like, and to a human microarray to determine if findings could be relevant in a human setting.ResultsImiquimod treatment induced a psoriasis-like skin inflammation. Resveratrol significantly diminished the severity of the psoriasis-like skin inflammation. The RNA microarray revealed a psoriasis-like gene expression-profile in the Imiquimod treated group, and highlighted several resveratrol dependent changes in relevant genes, such as increased expression of genes associated with retinoic acid stimulation and reduced expression of genes involved in IL-17 dependent pathways. Quantitative PCR confirmed a resveratrol dependent decrease in mRNA levels of IL-17A and IL-19; both central in developing psoriasis.ConclusionsResveratrol ameliorates psoriasis, and changes expression of retinoic acid stimulated genes, IL-17 signalling pathways, IL-17A and IL-19 mRNA levels in a beneficial manner, which suggests resveratrol, might have a role in the treatment of psoriasis and should be explored further in a human setting.

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Project description:CCR5 is a CC chemokine receptor involved in the migration of effector leukocytes including macrophages, NK, and T cells into inflamed tissues. Also, the role of CCR5 in CD4(+)Foxp3(+) regulatory T cell (Treg) homing has recently begun to grab attention. Japanese encephalitis (JE) is defined as severe neuroinflammation of the central nervous system (CNS) following infection with mosquito-borne flavivirus JE virus. However, the potential contribution of CCR5 to JE progression via mediating CD4(+)Foxp3(+) Treg homing has not been investigated.Infected wild-type (Ccr5(+/+)) and CCR5-deficient (Ccr5(-/-)) mice were examined daily for mortality and clinical signs, and neuroinflammation in the CNS was evaluated by infiltration of inflammatory leukocytes and cytokine expression. In addition, viral burden, NK- and JEV-specific T cell responses were analyzed. Adoptive transfer of CCR5(+)CD4(+)Foxp3(+) Tregs was used to evaluate the role of Tregs in JE progression.CCR5 ablation exacerbated JE without altering viral burden in the extraneural and CNS tissues, as manifested by increased CNS infiltration of Ly-6C(hi) monocytes and Ly-6G(hi) granulocytes. Compared to Ccr5(+/+) mice, Ccr5(-/-) mice unexpectedly showed increased responses of IFN-?(+)NK and CD8(+) T cells in the spleen, but not CD4(+) T cells. More interestingly, CCR5-ablation resulted in a skewed response to IL-17(+)CD4(+) Th17 cells and correspondingly reduced CD4(+)Foxp3(+) Tregs in the spleen and brain, which was closely associated with exacerbated JE. Our results also revealed that adoptive transfer of sorted CCR5(+)CD4(+)Foxp3(+) Tregs into Ccr5(-/-) mice could ameliorate JE progression without apparently altering the viral burden and CNS infiltration of IL-17(+)CD4(+) Th17 cells, myeloid-derived Ly-6C(hi) monocytes and Ly-6G(hi) granulocytes. Instead, adoptive transfer of CCR5(+)CD4(+)Foxp3(+) Tregs into Ccr5(-/-) mice resulted in increased expression of anti-inflammatory cytokines (IL-10 and TGF-?) in the spleen and brain, and transferred CCR5(+) Tregs were found to produce IL-10.CCR5 regulates JE progression via governing timely and appropriate CNS infiltration of CD4(+)Foxp3(+) Tregs, thereby facilitating host survival. Therefore, this critical and extended role of CCR5 in JE raises possible safety concerns regarding the use of CCR5 antagonists in human immunodeficiency virus (HIV)-infected individuals who inhabit regions in which both HIV and flaviviruses, such as JEV and West Nile virus, are endemic.

Dataset Information

PSORI-CM02 Formula Increases CD4+ Foxp3+ Regulatory T Cell Frequency and Ameliorates Imiquimod-Induced Psoriasis in Mice.

Publications

PSORI-CM02 Formula Increases CD4+ Foxp3+ Regulatory T Cell Frequency and Ameliorates Imiquimod-Induced Psoriasis in Mice.

Similar Datasets

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