Rapamycin ameliorates psoriasis by regulating the expression and methylation levels of tropomyosin viaERK1/2 andmTORpathways in vitro and in vivo

Abstract

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.

Poly (ADP‐ribose) polymerase 1 inhibition prevents neurodegeneration and promotes α‐synuclein degradation via transcription factor EB‐dependent autophagy in mutant α‐synucleinA53T model of Parkinson's disease

“…As a member of the MiT‐TFE helix‐loop‐helix leucine‐zipper (bHLH‐Zip) family of transcription factors, TFEB positively regulates autophagy and lysosome biogenesis. The activity of TFEB is modulated by protein translation modification, such as phosphorylation through mTOR, ERK, and AKT (Gao & Si, 2018; Palmieri et al., 2017), thus affecting the nuclear‐cytoplasmic shuttle of TFEB. In our study, accumulation of mutant α‐synucleinA53T led to over‐activation of PARP1, cytoplasm translocation of TFEB and autophagy dysfunction.…”

Differential Roles of the mTOR-STAT3 Signaling in Dermal γδ T Cell Effector Function in Skin Inflammation

“…Activation of mTOR signaling in psoriatic skin, particularly in keratinocytes, has been reported previously (Chamcheu et al, 2016). mTOR inhibitors have been tested in the animal models and clinic for the treatment of psoriasis (Bürger et al, 2017; Gao and Si, 2018). Preliminary data suggest that blocking mTOR signaling reduces disease severity (Wei and Lai, 2015).…”

Dysregulated epigenetic modifications in psoriasis

“…160 Topical application of 5-Za on mouse model shows amelioration of IMQ-induced epidermal thickening, suggesting a potential therapeutic use of methylation inhibitor on psoriasis. 161 Histone acetylation and deacetylation enzymes are another popular target in psoriasis treatment. HDAC inhibitor piperlongumine has been shown to alleviate IMQ-induced skin inflammation and keratinocyte hyperproliferation, 78 while another inhibitor trichostatin A has been shown to prevent T-cell differentiation towards pathogenic Th17 polarization.…”