MCC950, a selective NLPR3 inflammasome inhibitor, improves neurologic function and survival after cardiac arrest and resuscitation
Autor: | Zhuoran Wang, Wei Wang, Wei Yang, Xuan Li, Weiguo Zhang, Maorong Jiang, Huaxin Sheng, Jingjun Lyu, Ran Li, Jörn Karhausen |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Resuscitation Inflammasomes medicine.medical_treatment Immunology Interleukin-1beta Ischemia/reperfusion Spleen Pharmacology lcsh:RC346-429 Inflammasome 03 medical and health sciences Cellular and Molecular Neuroscience Mice 0302 clinical medicine Immune system NLRP3 Neuroinflammation NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Sterile inflammation Furans lcsh:Neurology. Diseases of the nervous system Sulfonamides business.industry General Neuroscience Research Interleukin Recovery of Function Cardiopulmonary Resuscitation Heart Arrest Blot Mice Inbred C57BL Survival Rate Disease Models Animal 030104 developmental biology Cytokine medicine.anatomical_structure Neurology Indenes CPR business 030217 neurology & neurosurgery Immunosuppression medicine.drug |
Zdroj: | Journal of Neuroinflammation, Vol 17, Iss 1, Pp 1-12 (2020) Journal of Neuroinflammation |
ISSN: | 1742-2094 |
Popis: | BackgroundCardiac arrest (CA) is associated with high morbidity and mortality, even after spontaneous circulation is re-established. This dire situation is partly due to post-CA syndrome for which no specific and effective intervention is available. One key component of post-CA syndrome is sterile inflammation, which affects various organs including the brain. A major effector of sterile inflammation is activated NLRP3 inflammasome, which leads to increased release of interleukin (IL)-1β. However, how NLRP3 inflammasome impacts neuroinflammation and neurologic outcome after CA is largely undefined.MethodsMice were subjected to a potassium-based murine CA and cardiopulmonary resuscitation (CPR) model. MCC950 was used to suppress activation of NLRP3 inflammasome after CA/CPR. Levels of protein and mRNA were examined by Western blotting and quantitative PCR, respectively. Immunologic changes were assessed by measuring cytokine expression and immune cell compositions. CA outcomes, including neurologic deficits, bacterial load in the lung, and survival rate, were evaluated.ResultsUsing our CA/CPR model, we found that NLRP3 inflammasome was activated in the post-CA brain, and that pro-inflammatory cytokine levels, including IL-1β, were increased. After treatment with MCC950, a potent and selective NLRP3 inflammasome inhibitor, mice exhibited improved functional recovery and survival rate during the 14-day observational period after CA/CPR. In line with these findings, IL-1β mRNA levels in the post-CA brain were significantly suppressed after MCC950 treatment. Interestingly, we also found that in MCC950- vs. vehicle-treated CA mice, immune homeostasis in the spleen was better preserved and bacterial load in the lung was significantly reduced.ConclusionsOur data demonstrate that activation of NLRP3 inflammasome could be a key event shaping the post-CA immuno- and neuro-pathology, and identify this pathway as a unique and promising therapeutic target to improve outcomes after CA/CPR. |
Databáze: | OpenAIRE |
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