Metformin inhibits IL-1β secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis

Gaku Tsuji, Akiko Hashimoto-Hachiya, Vu Hai Yen, Masaki Takemura, Ayako Yumine, Kazuhisa Furue, Masutaka Furue, Takeshi Nakahara
Cell Death Discovery 2020, 6: 11
Psoriasis is a systemic inflammatory disease significantly associated with comorbidities including type 2 diabetes mellitus (T2DM). Metformin is utilized as a first-line agent for treating T2DM. Although metformin reportedly inhibits mature IL-1β secretion via NLRP3 inflammasome in macrophages of T2DM patients, it remains unclear whether it affects skin inflammation in psoriasis. To test this, we analysed normal human epidermal keratinocytes (NHEKs), a major skin component, stimulated with the key mediators of psoriasis development, TNF-α and IL-17A. This stimulation induced the upregulation of pro-IL-1β mRNA and protein levels, and subsequently mature IL-1β secretion, which was inhibited by metformin treatment. To further reveal the mechanism involved, we examined how metformin treatment affected NLRP3 inflammasome activated by TNF-α and IL-17A stimulation. We found that this treatment downregulated caspase-1 expression, a key mediator of NLRP3 inflammasome. Furthermore, inhibitors of AMPK and SIRT1 abrogated the downregulation of caspase-1 induced by metformin treatment, indicating that AMPK and SIRT1 are essential for the inhibitory effect on NLRP3 inflammasome in NHEKs. As IL-1β stimulation induced upregulation of IL-36γ, CXCL1, CXCL2, CCL20, S100A7, S100A8 and S100A9 mRNA and protein levels in NHEKs, we examined whether metformin treatment affects such gene expression. Metformin treatment inhibited upregulation of IL-36γ, CXCL1, CXCL2, CCL20, S100A7, S100A8 and S100A9 mRNA and protein levels induced by TNF-α and IL-17A stimulation. Finally, we examined whether metformin administration affected psoriasis development in an imiquimod-induced mouse psoriasis model. Oral metformin treatment significantly decreased ear thickness, epidermal hyperplasia and inflammatory cell infiltration. A cytokine profile in the epidermis under metformin treatment showed that IL-1β, Cxcl1, Cxcl2, S100a7, S100a8 and S100A9 mRNA levels were downregulated compared with control levels. These results indicate that metformin administration prevented psoriasis development in vivo. Collectively, our findings suggest that metformin-mediated anti-psoriatic effects on the skin have the potential for treating psoriasis in T2DM patients.

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