摘要
Psoriasis is a systemic inflammatory disease that associatated with comorbidities including type 2 diabetes. Metformin is utilized as a first-line antidiabetic agent for the treatment of type 2 diabetes. Although metformin reportedly exhibits anti-inflammatory effects in various cells, the mechanism in the skin has not been determined. To reveal this, we examined whether metformin treatment affected the development of psoriasis in imiquimod (IMQ) -induced mouse psoriasis model. Oral treatment of metformin (20 mg/kg, daily) showed a significant decrease in ear swelling and epidermal hyperplasia. IL-17A-producing cell population was also significantly reduced in the metformin-treated group. We next analyzed a cytokine profile in the epidermis. The expression of Il1b, Il23, Il36γ, Cxcl1, Ccl20, S100a7, S100a8 and S100a9 were downregulated by metformin treatment. Because, the development of IMQ-psoriatic dermatitis is critically dependent on Tnf and Il17a, we next examined whether metformin modulated TNF-α and IL-17A induced inflammation using normal human epidermal keratinocytes. TNF-α and IL-17A stimulation upregulated expression of IL-1β, IL-23, IL-36γ, CXCL1, CCL20, S100A7, S100A8 and S100A9, which was inhibited by metformin treatment. Furthermore, metformin treatment downregulated caspase-1 expression, a key mediator of inflammasome. Consistent with this result, metformin treatment inhibited production of IL-1β induced by TNF-α and IL-17A stimulation. Finally, inhibition of AMPK and SIRT1function abrogated the downregulation of caspase-1 induced by metformin, indicating that activation of the AMPK-SIRT1 axis is essential for the inhibitory effect on inflammasome activation by metformin. Collectively, our findings suggest that activation of the AMPK-SIRT1 axis induced by metformin can be considered a potential strategy for the treatment of psoriasis.