Abstract
BackgroundThe NLRP3 inflammasome is a critical mediator of several vascular diseases through positive regulation of proinflammatory pathways. In this study, we defined the role of NLRP3 in both the acute and delayed phases following subarachnoid hemorrhage (SAH). SAH is associated with devastating early brain injury (EBI) in the acute phase, and those that survive remain at risk for developing delayed cerebral ischemia (DCI) due to cerebral vasospasm. Current therapies are not effective in preventing the morbidity and mortality associated with EBI and DCI. NLRP3 activation is known to drive IL-1β production and stimulate microglia reactivity, both hallmarks of SAH pathology; thus, we hypothesized that inhibition of NLRP3 could alleviate SAH-induced vascular dysfunction and functional deficits.MethodsWe studied NLRP3 in an anterior circulation autologous blood injection model of SAH in mice. Mice were randomized to either sham surgery + vehicle, SAH + vehicle, or SAH + MCC950 (a selective NLRP3 inhibitor). The acute phase was studied at 1 day post-SAH and delayed phase at 5 days post-SAH.ResultsNLRP3 inhibition improved outcomes at both 1 and 5 days post-SAH. In the acute (1 day post-SAH) phase, NLRP3 inhibition attenuated cerebral edema, tight junction disruption, microthrombosis, and microglial reactive morphology shift. Further, we observed a decrease in apoptosis of neurons in mice treated with MCC950. NLRP3 inhibition also prevented middle cerebral artery vasospasm in the delayed (5 days post-SAH) phase and blunted SAH-induced sensorimotor deficits.ConclusionsWe demonstrate a novel association between NLRP3-mediated neuroinflammation and cerebrovascular dysfunction in both the early and delayed phases after SAH. MCC950 and other NLRP3 inhibitors could be promising tools in the development of therapeutics for EBI and DCI.
Highlights
Inflammasomes are innate immune regulatory elements that drive the sterile inflammation characteristic of many disease states
MCC950 inhibits NLRP3 inflammasome activation 24 h post-subarachnoid hemorrhage (SAH) We first sought to confirm the efficacy of MCC950mediated NLRP3 inhibition in our SAH model
We investigated the role of NLRP3 inflammasome in SAHinduced neuroinflammation [17] and microglial reactivity [19, 36] as a contributor to vascular dysfunction after SAH
Summary
Inflammasomes are innate immune regulatory elements that drive the sterile inflammation characteristic of many disease states. In the presence of damage-associated molecular patterns (DAMPs) and other stimuli, inflammasomes are responsible for the proliferation of the immune response via regulating the post-translational processing of proinflammatory cytokines [1]. This action makes inflammasomes essential mediators of inflammatory diseases as well as ideal drug targets as their inhibition can prevent signal transduction and propagation early in the inflammatory cascade. SAH is associated with devastating early brain injury (EBI) in the acute phase, and those that survive remain at risk for developing delayed cerebral ischemia (DCI) due to cerebral vasospasm. NLRP3 activation is known to drive IL-1β production and stimulate microglia reactivity, both hallmarks of SAH pathology; we hypothesized that inhibition of NLRP3 could alleviate SAH-induced vascular dysfunction and functional deficits
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
