The Antidiabetic Agent Metformin Inhibits IL-23 Production in Murine Bone-Marrow-Derived Dendritic Cells.

Tomoyo Matsuda-Taniguchi,Akiko Hashimoto-Hachiya,Ayako Takai-Yumine,Masaki Takemura,Gaku Tsuji,Masutaka Furue,Takeshi Nakahara

doi:10.3390/jcm10235610

Tomoyo Matsuda-Taniguchi, Akiko Hashimoto-Hachiya + Show 5 more

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https://doi.org/10.3390/jcm10235610

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Abstract

Psoriasis is a chronic inflammatory skin disease, and its immune mechanism has been profoundly elucidated. Biologics targeting interleukin (IL)-23 have prevented the development of psoriasis. As major sources of IL-23, dendritic cells (DCs) play a pivotal role in psoriasis; however, the regulatory mechanism of IL-23 in DCs remains unclear. IL-36γ was reported to reflect the disease activity of psoriasis. Therefore, we hypothesized that IL-36γ may affect IL-23 production in DCs. To reveal the mechanism by which IL-36γ controls IL-23 production in DCs, we analyzed murine bone marrow-derived DCs (BMDCs) stimulated with IL-36γ. IL-36γ stimulation upregulated the mRNA and protein expression of Nfkbiz in BMDCs. Nfkbiz knockdown using siRNA transfection partially inhibited the upregulation of IL-23 mRNA expression induced by IL-36γ stimulation. Since NF-κB signaling regulates Nfkbiz expression and the anti-diabetic agent metformin reportedly modulates NF-κB signaling, we examined the effect of metformin treatment on IL-36γ-induced IL-23 production. Metformin treatment impaired the phosphorylation of NF-κB induced by IL-36γ stimulation with the subsequent downregulation of Nfkbiz, resulting in the inhibition of IL-23 production in BMDCs. These data provided evidence that metformin treatment can inhibit IL-36γ-mediated IL-23 production in BMDCs, which might contribute to the prevention of psoriasis.

Highlights

IntroductionPsoriasis is an immune-mediated inflammatory skin disease affecting 2–4% of the global population [1]
Published: 29 November 2021Psoriasis is an immune-mediated inflammatory skin disease affecting 2–4% of the global population [1]
To investigate the mechanism by which IL-36γ regulates IL-23 expression in dendritic cells (DCs), we analyzed murine bone marrow-derived DCs (BMDCs) stimulated with IL-36γ. quantitative reverse transcription (qRT)-PCR analysis revealed that IL-36γ

Summary

Introduction

Psoriasis is an immune-mediated inflammatory skin disease affecting 2–4% of the global population [1]. The pathology of psoriasis is characterized by epidermal hyperproliferation, the intraepidermal accumulation of neutrophils, and the infiltration of dermal inflammatory cells such as T-cells, macrophages, and dendritic cells (DCs) [3]. Among these immune cells, DC counts are increased significantly in psoriatic lesions [4]. Autoantigens from keratinocytes activate plasmacytoid DCs (pDCs) in the dermis. PDCs produce type I interferon and tumor necrosis factor-α, which activates classical DCs (cDCs), resulting in interleukin (IL)-23 secretion. IL-23 is mostly produced by cDCs, which correspond to CD1c+ DCs in humans.

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