Time-dependent dual effect of NLRP3 inflammasome in brain ischaemia.

Autor: Palomino-Antolin A; Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain.; Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, UAM, Madrid, Spain., Narros-Fernández P; Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain.; Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, UAM, Madrid, Spain., Farré-Alins V; Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain.; Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, UAM, Madrid, Spain., Sevilla-Montero J; Instituto de Investigacion Sanitaria Princesa (IIS-IP), Department of Medicine, School of Medicine, Universidad Autonoma of Madrid, Madrid, Spain., Decouty-Pérez C; Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain.; Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, UAM, Madrid, Spain., Lopez-Rodriguez AB; Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain.; Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, UAM, Madrid, Spain., Fernández N; Fluorescence Imaging Group, Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain., Monge L; Fluorescence Imaging Group, Departamento de Fisiología, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain., Casas AI; Department of Pharmacology and Personalised Medicine, MHeNs, Maastricht University, Maastricht, The Netherlands.; Department of Neurology, University Clinics Essen, Essen, Germany., Calzada MJ; Instituto de Investigacion Sanitaria Princesa (IIS-IP), Department of Medicine, School of Medicine, Universidad Autonoma of Madrid, Madrid, Spain., Egea J; Molecular Neuroinflammation and Neuronal Plasticity Research Laboratory, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria-Hospital Universitario de la Princesa, Madrid, Spain.; Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, UAM, Madrid, Spain.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2022 Apr; Vol. 179 (7), pp. 1395-1410. Date of Electronic Publication: 2022 Feb 05.
DOI: 10.1111/bph.15732
Abstrakt: Background: Inflammasomes are cytosolic multiprotein complexes which, upon assembly, activate the maturation and secretion of the inflammatory cytokines IL-1β and IL-18. However, participation of the NLRP3 inflammasome in ischaemic stroke remains controversial. Our aims were to determine the role of NLRP3 in brain ischaemia, and explore the mechanism involved in the potential protective effect of the neurovascular unit.
Methods: WT and NLRP3 knock-out mice were subjected to ischaemia by middle cerebral artery occlusion (60 min) with or without treatment with MCC950 at different time points post-stroke. Brain injury was measured histologically with 2,3,5-triphenyltetrazolium chloride (TTC) staining.
Results: We identified a time-dependent dual effect of NLRP3. While neither the pre-treatment with MCC950 nor the genetic approach (NLRP3 KO) proved to be neuroprotective, post-reperfusion treatment with MCC950 significantly reduced the infarct volume in a dose-dependent manner. Importantly, MCC950 improved the neuro-motor function and reduced the expression of different pro-inflammatory cytokines (IL-1β and TNF-α), NLRP3 inflammasome components (NLRP3 and pro-caspase-1), protease expression (MMP9), and endothelial adhesion molecules (ICAM and VCAM). We observed a marked protection of the blood-brain barrier (BBB), which was also reflected in the recovery of the tight junction proteins (ZO-1 and Claudin-5). Additionally, MCC950 produced a reduction of the CCL2 chemokine in blood serum and in brain tissue, which lead to a reduction in the immune cell infiltration.
Conclusions: These findings suggest that post-reperfusion NLRP3 inhibition may be an effective acute therapy for protecting the blood-brain barrier in cerebral ischaemia with potential clinical translation.
(© 2021 The British Pharmacological Society.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje