Methotrexate restores the function of peripheral blood regulatory T cells in psoriasis vulgaris via the CD73/AMPK/mTOR pathway

Yan, Kexiang; Xu, Wenping; Huang, Yuxian; Zhang, Z.; Huang, Qiong; Xin, Kevin; Ma, Yan; Han, Ling

doi:10.1111/bjd.16560

Cited by 48 publications

(43 citation statements)

References 31 publications

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“…CD4 + CD25 + Foxp3 + Tregs can differentiate into IL-17A-producing Th17 cells in patients with psoriasis ( 64 ). Previous studies have shown that induction of endogenous CD4 + CD25 + Foxp3 + Tregs or reversal of Th17/Treg imbalance ameliorates IMQ-induced psoriasis in mice ( 65 , 66 ). CD4 + Foxp3 + Tregs could circulate through the lymphoid tissues, such as draining lymph nodes, resulting in suppression of effector T cell activation and immune responses in skin ( 67 ).…”

Section: Discussionmentioning

confidence: 99%

Esculetin Ameliorates Psoriasis-Like Skin Disease in Mice by Inducing CD4+Foxp3+ Regulatory T Cells

et al. 2018

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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.

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Section: Discussionmentioning

confidence: 99%

Esculetin Ameliorates Psoriasis-Like Skin Disease in Mice by Inducing CD4+Foxp3+ Regulatory T Cells

et al. 2018

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“…Methotrexate (MTX), a common immunosuppressant, has been frequently utilized to treat psoriasis . MTX has been shown to exert its therapeutic effects on psoriasis via restoring CD4 + CD25 + FoxP3 + T reg function . Interestingly, we have also found previously that kaempferol suppresses alloimmune responses and promotes transplantation tolerance by sustaining CD4 + FoxP3 + T regs .…”

Section: Discussionmentioning

confidence: 77%

“…Recent studies have shown that there is a defect in T reg suppressive capacity or function in psoriasis . Methotrexate (MTX), a common immunosuppressant, has been frequently utilized to treat psoriasis .…”

Section: Discussionmentioning

confidence: 99%

Kaempferol attenuates imiquimod-induced psoriatic skin inflammation in a mouse model

Liu

et al. 2019

Clinical and Experimental Immunology

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Psoriasis is an immune-mediated inflammatory skin disease that mainly affects the skin barrier. Treatment for psoriasis mainly includes conventional immunosuppressive drugs. However, long-term treatment with global immunosuppressive agents may cause a variety of side effects, including nephrotoxicity and infections. Kaempferol, a natural flavonol present in various plants, is known to possess potent anti-inflammatory, anti-oxidant and anti-cancerous properties. However, it is unknown whether kaempferol is also anti-psoriatic. Here we established an imiquimod (IMQ)-induced psoriatic mouse model to explore the potential therapeutic effects of kaempferol on psoriatic skin lesions and inflammation. In this study, we demonstrated that treatment with kaempferol protected mice from developing psoriasis-like skin lesions induced by topical administration of IMQ. Kaempferol reduced CD3 + T cell infiltration and gene expression of major proinflammatory cytokines, including interleukin (IL)-6, IL-17A and tumor necrosis factor (TNF)-α, in the psoriatic skin lesion. It also down-regulated proinflammatory nuclear factor kappa B (NF-κB) signaling in the skin. The therapeutic effects were associated with a significant increase in CD4 + forkhead box protein 3 (FoxP3) + regulatory T cell (T reg ) frequency in the spleen and lymph nodes as well as FoxP3-positive staining in the skin lesion. Conversely, depletion of CD4 + CD25 + T regs reversed the therapeutic effects of kaempferol on the skin lesion. Kaempferol also lowered the percentage of IL-17A + CD4 + T cells in the spleen and lymph nodes of IMQ-induced psoriatic mice. Finally, kaempferol suppressed the proliferation of T cells in vitro and their mTOR signaling. Thus, our findings suggest that kaempferol may be a therapeutic drug for treating human psoriasis in the near future.

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“…This issue of the BJD includes an interesting article in the translational research section. The study by Yan et al . extends our understanding of mechanisms of MTX in psoriasis treatment.…”

mentioning

confidence: 80%

What's new about the mechanism of methotrexate action in psoriasis?

Chen

2018

Br J Dermatol

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Methotrexate restores the function of peripheral blood regulatory T cells in psoriasis vulgaris via the CD73/AMPK/mTOR pathway

Abstract: We speculate that MTX can restore the immunosuppressive function of Tregs through upregulating CD73, activating AMPK and inactivating the mTOR pathway. These findings may partly explain the mechanism by which MTX treats psoriasis.

Cited by 48 publications

References 31 publications

Esculetin Ameliorates Psoriasis-Like Skin Disease in Mice by Inducing CD4+Foxp3+ Regulatory T Cells

Esculetin Ameliorates Psoriasis-Like Skin Disease in Mice by Inducing CD4+Foxp3+ Regulatory T Cells

Kaempferol attenuates imiquimod-induced psoriatic skin inflammation in a mouse model

What's new about the mechanism of methotrexate action in psoriasis?

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