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Int Immunopharmacol. 2019 Jun 13;74:105682. doi: 10.1016/j.intimp.2019.105682. [Epub ahead of print]

Inhibition of NLRP3 inflammasome-mediated pyroptosis in macrophage by cycloastragenol contributes to amelioration of imiquimod-induced psoriasis-like skin inflammation in mice.

Author information

1
State Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China.
2
Affiliated Hospital of Nanjing University of Chinese Medicine, 155 Hanzhong Road, Nanjing 210029, China.
3
School of Medicine, Shenzhen University, 1066 Xueyuan Avenue, Shenzhen 518055, China.
4
Jiangsu Yongjian Pharmaceutical Co., Ltd., 1 Yaocheng Avenue, China Medical City, Taizhou 225300, China.
5
School of Medicine, Shenzhen University, 1066 Xueyuan Avenue, Shenzhen 518055, China. Electronic address: xmwang@szu.edu.cn.
6
State Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China. Electronic address: xiaoyun.ji@nju.edu.cn.
7
State Key Laboratory of Pharmaceutical Biotechnology, Department of Biotechnology and Pharmaceutical Sciences, School of Life Sciences, Nanjing University, 163 Xianlin Avenue, Nanjing 210023, China. Electronic address: yangsun@nju.edu.cn.

Abstract

Psoriasis is a common chronic inflammatory skin disease, and the infiltrated macrophages in psoriatic skin lesions play a key role in the progression of this uncontrolled cutaneous inflammation. However, the current therapeutic strategies for patients with psoriasis are not satisfactory. Here, we report that cycloastragenol (CAG), a natural active small compound isolated from Astragalus membranaceus, significantly ameliorated imiquimod (IMQ)-induced psoriasiform dermatitis in mice by targeting proinflammatory macrophages. CAG significantly reduced the clinical scores, decreased the epidermal thickness, and ameliorated the deteriorating histopathology observed in IMQ-induced mice. CAG treatment specifically reduced the dermal infiltration of macrophages, rather than of dendritic cells, neutrophils, or T lymphocytes, into psoriatic skin. CAG dose-dependently decreased the level of proinflammatory cytokines, including IL-1β, TNF-α and IL-6, in murine psoriatic skin and serum, as well as in IMQ-stimulated, bone-marrow-derived macrophages. When compared to the control group, CAG significantly decreased IMQ-triggered NLRP3 inflammasome activation and gasdermin D-mediated cell pyroptosis in these proinflammatory macrophages. CAG also suppressed the assembly of the NLRP3 inflammasome complex. Taken together, the results show that CAG selectively modulates macrophage function by inhibiting NLRP3 inflammasome-mediated pyroptosis to ameliorate IMQ-induced psoriasis-like skin inflammation in mice. Our findings also identify an effective drug candidate for the treatment of psoriasis.

KEYWORDS:

Cycloastragenol; Imiquimod; NLRP3 inflammasome; Psoriasis; Pyroptosis

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