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

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.

New Pathways for the Skin's Stress Response: The Cholinergic Neuropeptide SLURP-1 Can Activate Mast Cells and Alter Cytokine Production in Mice

“…Regulation of NLRP3 inflammasome activation could represent a target for future pharmacologic interventions employing SLURP-1. This is especially interesting in chronic inflammatory skin and allergic diseases ( 107 ) that reportedly are stress-sensitive and involve NLRP3 inflammasome activation such as psoriasis ( 108 ), contact hypersensitivity ( 109 ) or asthma ( 110 ). In fact, in a microarray analysis employing the Affymetrix Mouse Genome 430A 2.0 Array that we had performed in another project ( 6 ), we had previously observed the as yet unreported upregulation of Asc (1.280-fold) and Casp1 (0.397-fold).…”

Nutraceutical Strategies for Suppressing NLRP3 Inflammasome Activation: Pertinence to the Management of COVID-19 and Beyond

“…Inflammasomes are suspected to play a pathogenic role in the complications of diabetes, in a host of neurodegenerative disorders, in autoimmune disorders including rheumatoid arthritis, and in periodontal disease [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Inflammasomes contribute to the pathogenesis of chronic skin disorders such as psoriasis and acne [ 20 , 21 , 22 , 23 ]. They have also been linked to asthma and allergic inflammation [ 24 , 25 , 26 , 27 ].…”

A Molecular Perspective on the Potential Benefits of Metformin for the Treatment of Inflammatory Skin Disorders

“…First, AMP-activated protein kinase has been shown to exert anti-inflammatory effects in macrophages [43]. It has also been reported that metformin treatment results in decreased inflammatory markers and cytokines such as tumor necrosis factor alpha (TNF-α) and IL-1β [44]. In the keratinocytes corresponding to the epidermal tissue, it has been found that metformin reduces cell proliferation through the mitogen-activated protein kinase (MAPK) signaling pathway [45].…”