NLRP3 inflammasome-mediated microglial pyroptosis is critically involved in the development of post-cardiac arrest brain injury

• Published in: Journal of neuroinflammation Vol. 17; no. 1; pp. 1 - 219
• Main Authors: Chang, Yuan, Zhu, Juan, Wang, Di, Li, Hua, He, Yihua, Liu, Kewei, Wang, Xiaoqiang, Peng, Yuqin, Pan, Suyue, Huang, Kaibin
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 23.07.2020; BioMed Central; BMC
• Subjects: Apoptosis; Brain injuries; Brain injury; Cardiac arrest; Cardiopulmonary resuscitation; Caspase-1; Catheters; Causes of; CD11b antigen; Cell death; Complications and side effects; CPR; Cytokines; Experiments; Flow cytometry; Health aspects; Heart; Immunofluorescence; Immunoprecipitation; Infiltration; Inflammasomes; Inflammation; Laboratory animals; Leukocytes; Medical prognosis; Microglia; NLRP3; NOD-like receptors; Physiological aspects; Polymerase chain reaction; Pyroptosis; Traumatic brain injury; Ventilators; Western blotting; China
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-020-01879-1

Abstract Background Brain injury is the leading cause of death and disability in survivors of cardiac arrest, where neuroinflammation is believed to play a pivotal role, but the underlying mechanism remains unclear. Pyroptosis is a pro-inflammatory form of programmed cell death that triggers inflammatory response upon infection or other stimuli. This study aims to understand the role of microglial pyroptosis in post-cardiac arrest brain injury. Methods Sprague-Dawley male rats underwent 10-min asphyxial cardiac arrest and cardiopulmonary resuscitation or sham-operation. Flow cytometry analysis, Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR), co-immunoprecipitation, and immunofluorescence were used to evaluate activated microglia and CD11b-positive leukocytes after cardiac arrest and assess inflammasome activation and pyroptosis of specific cellular populations. To further explore the underlying mechanism, MCC950 or Ac-YVAD-cmk was administered to block nod-like receptor family protein 3 (NLRP3) or caspase-1, respectively. Results Our results showed that, in a rat model, successful resuscitation from cardiac arrest resulted in microglial pyroptosis and consequential inflammatory infiltration which was mediated by the activation of NLRP3 inflammasome. Targeting NLRP3 and caspase-1, the executor of pyroptosis, with selective inhibitors MCC950 and Ac-YVAD-cmk treatment significantly prevented microglial pyroptosis, reduced infiltration of leukocytes, improved neurologic outcome, and alleviated neuro-pathological damages after cardiac arrest in modeling rats. Conclusions This study demonstrates that microglial pyroptosis mediated by NLRP3 inflammasome is critically involved in the pathogenesis of post-cardiac arrest brain injury and provides a new therapeutic strategy.