PMID- 32194991 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230926 IS - 2058-7716 (Print) IS - 2058-7716 (Electronic) IS - 2058-7716 (Linking) VI - 6 DP - 2020 TI - Metformin inhibits IL-1beta secretion via impairment of NLRP3 inflammasome in keratinocytes: implications for preventing the development of psoriasis. PG - 11 LID - 10.1038/s41420-020-0245-8 [doi] LID - 11 AB - 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-1beta 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-alpha and IL-17A. This stimulation induced the upregulation of pro-IL-1beta mRNA and protein levels, and subsequently mature IL-1beta secretion, which was inhibited by metformin treatment. To further reveal the mechanism involved, we examined how metformin treatment affected NLRP3 inflammasome activated by TNF-alpha 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-1beta stimulation induced upregulation of IL-36gamma, 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-36gamma, CXCL1, CXCL2, CCL20, S100A7, S100A8 and S100A9 mRNA and protein levels induced by TNF-alpha 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-1beta, 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. CI - (c) The Author(s) 2020. FAU - Tsuji, Gaku AU - Tsuji G AD - 1Research and Clinical Center for Yusho and Dioxin, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582 Japan. ISNI: 0000 0001 2242 4849. GRID: grid.177174.3 AD - 2Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582 Japan. ISNI: 0000 0001 2242 4849. GRID: grid.177174.3 FAU - Hashimoto-Hachiya, Akiko AU - Hashimoto-Hachiya A AD - 2Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582 Japan. ISNI: 0000 0001 2242 4849. GRID: grid.177174.3 FAU - Yen, Vu Hai AU - Yen VH AD - 2Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582 Japan. ISNI: 0000 0001 2242 4849. GRID: grid.177174.3 FAU - Takemura, Masaki AU - Takemura M AD - 2Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582 Japan. ISNI: 0000 0001 2242 4849. GRID: grid.177174.3 FAU - Yumine, Ayako AU - Yumine A AD - 1Research and Clinical Center for Yusho and Dioxin, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582 Japan. ISNI: 0000 0001 2242 4849. GRID: grid.177174.3 FAU - Furue, Kazuhisa AU - Furue K AD - 2Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582 Japan. ISNI: 0000 0001 2242 4849. GRID: grid.177174.3 FAU - Furue, Masutaka AU - Furue M AD - 1Research and Clinical Center for Yusho and Dioxin, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582 Japan. ISNI: 0000 0001 2242 4849. GRID: grid.177174.3 AD - 2Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582 Japan. ISNI: 0000 0001 2242 4849. GRID: grid.177174.3 AD - 3Division of Skin Surface Sensing, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582 Japan. ISNI: 0000 0001 2242 4849. GRID: grid.177174.3 FAU - Nakahara, Takeshi AU - Nakahara T AD - 2Department of Dermatology, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582 Japan. ISNI: 0000 0001 2242 4849. GRID: grid.177174.3 AD - 3Division of Skin Surface Sensing, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashiku, Fukuoka, 812-8582 Japan. ISNI: 0000 0001 2242 4849. GRID: grid.177174.3 LA - eng PT - Journal Article DEP - 20200304 PL - United States TA - Cell Death Discov JT - Cell death discovery JID - 101665035 PMC - PMC7055596 OTO - NOTNLM OT - Inflammasome OT - Skin diseases COIS- Conflict of interestThe authors declare that they have no conflict of interest. EDAT- 2020/03/21 06:00 MHDA- 2020/03/21 06:01 PMCR- 2020/03/04 CRDT- 2020/03/21 06:00 PHST- 2019/08/18 00:00 [received] PHST- 2020/02/14 00:00 [revised] PHST- 2020/02/14 00:00 [accepted] PHST- 2020/03/21 06:00 [entrez] PHST- 2020/03/21 06:00 [pubmed] PHST- 2020/03/21 06:01 [medline] PHST- 2020/03/04 00:00 [pmc-release] AID - 245 [pii] AID - 10.1038/s41420-020-0245-8 [doi] PST - epublish SO - Cell Death Discov. 2020 Mar 4;6:11. doi: 10.1038/s41420-020-0245-8. eCollection 2020.