Blocking mTOR Signalling with Rapamycin Ameliorates Imiquimod-induced Psoriasis in Mice

Bürger, Claudia; Shirsath, Nitesh; Lang, Victoria; Diehl, Sandra; Kaufmann, Roland; Weigert, Andreas; Han, Yingying; Ringel, Christian; Wolf, Peter

doi:10.2340/00015555-2724

Cited by 54 publications

(48 citation statements)

References 40 publications

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“…It has also been reported that suppression of mTOR signaling induces T regs . Moreover, previous studies have shown that hyperactivated mTORC1 signaling is an important aspect in psoriasis and that blocking mTOR signaling ameliorates IMQ‐induced psoriasis in mice. Thus, we investigated whether kaempferol would have an impact on T cell proliferation and their mTOR signaling.…”

Section: Resultsmentioning

confidence: 92%

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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Section: Resultsmentioning

confidence: 92%

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

Liu

et al. 2019

Clinical and Experimental Immunology

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“…Given that there is currently limited therapy in SpA, these results may support efforts to evaluate the efficacy of rapamycin treatment for SpA patients. Rapamycin has also been found to reduce inflammation in animal models of psoriasis (62) and colitis (18,63). These disease manifestations can co-occur with SpA and have overlapping disease mechanisms with SpA (1).…”

Section: Discussionmentioning

confidence: 99%

mTOR Blockade by Rapamycin in Spondyloarthritis: Impact on Inflammation and New Bone Formation in vitro and in vivo

et al. 2020

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Conclusion: mTOR blockade inhibits IL-17A and TNFα production by PBMCs, and osteogenic differentiation of FLS from patients with SpA in vitro. In the HLA-B27 transgenic rat model of SpA, rapamycin inhibits arthritis and spondylitis development and severity, reduces articular bone erosions, decreases pathologic new bone formation and suppresses IL-17A expression. These results may support efforts to evaluate the efficacy of targeting the mTOR pathway in SpA patients.

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“…Rapamycin, an inhibitor of mTOR, was reported to ameliorate the IMQ‐induced psoriasis in mice by blocking the mTOR signalling pathway . And the mTOR signalling pathway was reported to regulate divergent functions of immune cells, including the differentiation of Th1/Th17, leucocyte trafficking and so on .…”

Section: Discussionmentioning

confidence: 99%

“…And the mTOR signalling pathway was reported to regulate divergent functions of immune cells, including the differentiation of Th1/Th17, leucocyte trafficking and so on . Recently, increasing evidences have shown that mTOR pathway was activated in the lesional skin of psoriasis, suggesting it may be involved in the pathogenesis of psoriasis . Therefore, RAPA (the inhibitor of mTOR) was initially investigated as a potential agent for the psoriasis patients, and several studies demonstrated that RAPA can ameliorate the IMQ‐induced psoriasis in mice .…”

Section: Discussionmentioning

confidence: 99%

“…Recently, increasing evidences have shown that mTOR pathway was activated in the lesional skin of psoriasis, suggesting it may be involved in the pathogenesis of psoriasis . Therefore, RAPA (the inhibitor of mTOR) was initially investigated as a potential agent for the psoriasis patients, and several studies demonstrated that RAPA can ameliorate the IMQ‐induced psoriasis in mice . However, the underlying mechanisms of RAPA effects on psoriasis remain undetermined.…”

Section: Discussionmentioning

confidence: 99%

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Rapamycin ameliorates psoriasis by regulating the expression and methylation levels of tropomyosin via ERK1/2 and mTOR pathways in vitro and in vivo

Gao

2018

Experimental Dermatology

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Psoriasis is a chronic inflammatory disease, affecting more than millions of people in the world. Recently, the mTOR inhibitor rapamycin (RAPA) was reported to be involved in the pathogenesis of psoriasis. However, the underlying mechanism remains unclear. Haematoxylin and eosin staining was used to examine the effects of RAPA on inflammatory level of lesional tissues from patients with psoriasis and animal models. Quantitative real-time PCR, immunohistochemistry and western blot assay were performed to assess the effects of RAPA on tropomyosins (TPMs) expression in patients with psoriasis, cell models and animal models. Phalloidin staining was used to assess the RAPA effects on cell skeleton. The effects of RAPA on cell proliferation and cell cycle were detected by CCK-8 assay, EdU staining and flow cytometry. Methylation status of TPMs was analysed by methylation-specific PCR. The expression of TPM1 and TPM2 was significantly downregulated, while their methylation level was obviously higher in the lesional tissues, cell models and animal models of psoriasis. After treated with RAPA, the expression and methylation levels of TPMs were all restored in the cell models and animal models of psoriasis. RAPA inhibited cell proliferation and decreased the ratio of S phase cell in Hacat or human epidermal keratinocytes cell models of psoriasis. Finally, the activated ERK1/2 and mTOR pathways in the cell model and animal model of psoriasis were suppressed by the treatment of RAPA. RAPA could be used as an effective agent for the treatment of psoriasis by decreasing the methylation level of TPM1 and TPM2 via inhibiting the ERK1/2 and mTOR signalling pathways.

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Blocking mTOR Signalling with Rapamycin Ameliorates Imiquimod-induced Psoriasis in Mice

Cited by 54 publications

References 40 publications

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

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

mTOR Blockade by Rapamycin in Spondyloarthritis: Impact on Inflammation and New Bone Formation in vitro and in vivo

Rapamycin ameliorates psoriasis by regulating the expression and methylation levels of tropomyosin via ERK1/2 and mTOR pathways in vitro and in vivo

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