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The artemisinin analog SM934 alleviates dry eye disease in rodent models by regulating TLR4/NF-κB/NLRP3 signaling

Authors: Fang-ming Yang1,2, Di Fan1,2, Xiao-qian Yang2, Feng-hua Zhu2, Mei-juan Shao1,2, Qian Li2, Yu-ting Liu2,3, Ze-min Lin2, Shi-qi Cao2,3, Wei Tang2,3, Shi-jun He2,3, Jian-ping Zuo1,2,3
1 Laboratory of Immunology and Virology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
2 Laboratory of Immunopharmacology, State Key
3 University of Chinese Academy of Sciences, Beijing 100049, China
Correspondence to: Shi-jun He: heshijun@simm.ac.cn, Jian-ping Zuo: jpzuo@simm.ac.cn,
DOI: 10.1038/s41401-020-0484-5
Received: 20 May 2020
Accepted: 15 July 2020
Advance online: 3 August 2020

Abstract

Dry eye disease (DED) is a multifactorial disorder of the tears and ocular surface characterized by manifestations of dryness and irritation. Although the pathogenesis is not fully illuminated, it is recognized that inflammation has a prominent role in the development and deterioration of DED. β-aminoarteether maleate (SM934) is a water-soluble artemisinin derivative with antiinflammatory and immunosuppressive activities. In this study, we established scopolamine hydrobromide (SCOP)-induced rodent model as well as benzalkonium chloride (BAC)-induced rat model to investigate the therapeutic potential of SM934 for DED. We showed that topical application of SM934 (0.1%, 0.5%) significantly increased tear secretion, maintained the number of conjunctival goblet cells, reduced corneal damage, and decreased the levels of inflammatory mediators (TNF-α, IL-6, IL-10, or IL-1β) in conjunctiva in SCOP-induced and BAC-induced DED models. Moreover, SM934 treatment reduced the accumulation of TLR4- expressing macrophages in conjunctiva, and suppressed the expression of inflammasome components, i.e., myeloid differentiation factor88 (MyD88), Nod-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing CARD (ASC), and cleaved caspase 1. In LPS-treated RAW 264.7 cells, we demonstrated that pretreatment with SM934 (10 μM) impeded the upregulation of TLR4 and downstream NF-κB/NLRP3 signaling proteins. Collectively, artemisinin analog SM934 exerts therapeutic benefits on DED by simultaneously reserving the structural integrity of ocular surface and preventing the corneal and conjunctival inflammation, suggested a further application of SM934 in ophthalmic therapy, especially for DED.
Keywords: dry eye disease; artemisinin derivative; β-aminoarteether maleate; inflammation; macrophages; TLR4; inflammasome

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