Abstract
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.
Highlights
Psoriasis is a common chronic inflammatory disease of the skin affecting 0.6–3% of the global population[1,2,3]
We found that metformin treatment downregulated caspase-1 expression, resulting in reduced mature IL-1β secretion in normal human epidermal keratinocytes (NHEKs), via a mechanism that was dependent on SIRT1, a nicotinamide adenine dinucleotide-dependent deacetylase and a target molecule activated by metformin[33]
We examined whether metformin treatment affected the expression of these genes in tumour necrosis factor (TNF)-α- and IL17A-stimulated NHEKs, and found that it inhibited the upregulation of IL-1β, IL-36γ, CXCL1, CXCL2, CCL20, S100A7, S100A8 and S100A9 mRNA and protein levels induced by TNF-α and IL-17A stimulation
Summary
Psoriasis is a common chronic inflammatory disease of the skin affecting 0.6–3% of the global population[1,2,3]. Tsuji et al Cell Death Discovery (2020)6:11 such as type 2 diabetes mellitus (T2DM)[5,6,7,8], arterial hypertension[9,10], obesity[11,12,13] and cardiovascular disease[14,15,16]. Several retrospective epidemiological studies have shown the association of T2DM with psoriasis and suggested that there is a severity-dependent relationship[7,8]. One clinical study has shown that the long-term use of metformin was associated with a reduced risk of psoriasis[21]
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