HMGB1 promotes the activation of NLRP3 and caspase-8 inflammasomes via NF-κB pathway in acute glaucoma

Background: acute glaucoma is a significantly sight-threatening cause of irreversible blindness in the world characterized by a sudden and substantial intraocular pressure (iop) increase and subsequent retinal ganglion cell (rgc) death. this study aims to explore the role of high-mobility group box 1 (hmgb1) in an acute glaucoma mouse model. methods: an acute glaucoma model was induced by a rapid and substantial increase iop to 70 mmhg for 60 min via anterior chamber punctured and affused with balance salt solution in c57bl/6 mice. retinal tissue ischemic damage and loss of rgcs were assessed at 6,24,48,72 h after high iop treatment,and at 48 h,group with or without recombinant high-mobility group box 1 (rhmgb1),the hmgb1 inhibitor,glycyrrhizic acid (ga),and by he and immunofluorescent staining. the nuclear factor κb (nf-κb) inhibitor,jsh-23,and caspase-8 inhibitor,z-ietd-fmk,were injected into vitreous. reverse transcription and semi-quantitative reverse transcription polymerase chain reaction (rt-pcr),western blotting,and immunoprecipitation were performed to evaluate the expression level of nucleotide-binding domain,leucine-rich repeat containing protein 3 (nlrp3),phosphor-nf-κb p65,caspase-8,caspase-1,apoptosis-associated speck-like protein containing a card (asc),and interleukin-1β (il-1β). results: hmgb1 was increased in ischemic retinal tissue during acute glaucoma as early as 6 h after rapid iop elevation. exogenous hmgb1 exacerbated retinal ischemic damage,rgc loss,and inhibition of endogenous hmgb1 significantly reduced the severity of disease. hmgb1 significantly induced the elevation of canonical nlrp3,asc,caspase-1,and non-canonical capase-8-asc inflammasome and promoted the processing of il-1β. furthermore,the effect of hmgb1 on nlrp3 inflammasome activation and il-1β production was dependent on nf-κb pathway. thus,hmgb1/caspase-8 pathway promoted the processing of il-1β via nf-κb pathway. conclusion: the findings of this study identified a novel signaling pathway in which hmgb1,in response to acutely elevated intraocular pressure,activated the canonical nlrp3 and non-canonical caspase-8 inflammasomes and production of il-1β during acute glaucoma development. these results provide new insights to the understanding of the innate response that contributes to pathogenesis of acute glaucoma. © 2015 chi et al.