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

摘要

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 anti-inflammatory 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-KB/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.