Purchase this article with an account.
Hui Chen, Wei Chi; NLRC4 magnifies inflammatory cascades via maturation of IL-1β, which in turn promotes caspase-8-dependent NLRs activation in dry eye.. Invest. Ophthalmol. Vis. Sci. 2018;59(9):3809.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
To explore the functions and mechanisms whereby NLRC4 mediates the innate immunity and its associtation with caspase-8 in the pathogenesis of dry eye-induced ocular surface disorders.
We used a murine model and human cornea epithelia treated with desiccating stress (DS) to mimic pathophysiology of dry eye to investigate NLRs regulation in innate immunity.
We demonstrated that DS exacerbated ocular surface disorders by less tear production, delayed wound healing or even corneal perforation. DS also triggered caspase-8 (C8) activation via TLR4 to promote NLRC4 activation, driving caspase-1 (C1) to cleave pro-IL-1β into mature form. Our study also validated that inhibiting the activation of C8 and NLRC4 inflammasome significantly attenuated DS-induced ocular surface disorders. One unanticipated finding was that overexpression of C1 and mature IL-1β in turn elevated C8 production so as to activate NLRC4, boosting inflammatory cascades in initiation of innate immunity.
Our findings disclosed that TLR4 signaling contributed to C8 activation to enhance NLRC4 inflammasome expression, processing mature IL-1β to aggravate ocular surface damage in DS. Furthermore, we firstly uncovered that C1-dependent maturation of IL-1β in turn elevated C8 to activate NLRC4, forming a regulative circuit to magnify inflammatory cascades in dry eye. Knocking down C8 and NLRC4 improved DS-induced corneal damage, all of which could be potential therapeutic targets and strategies for dry eye.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
This PDF is available to Subscribers Only