| Autor: |
Palomino-Antolín A; Unidad de Investigación, Hospital Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain., Decouty-Pérez C; Unidad de Investigación, Hospital Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain., Farré-Alins V; Unidad de Investigación, Hospital Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain., Narros-Fernández P; Unidad de Investigación, Hospital Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain., Lopez-Rodriguez AB; Unidad de Investigación, Hospital Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain., Álvarez-Rubal M; Unidad de Investigación, Hospital Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain., Valencia I; Unidad de Investigación, Hospital Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain., López-Muñoz F; Faculty of Health, Camilo José Cela University of Madrid (UCJC), 28692 Madrid, Spain.; Neuropsychopharmacology Unit, Hospital 12 de Octubre Research Institute, 28041 Madrid, Spain., Ramos E; Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Complutense University of Madrid, 28040 Madrid, Spain., Cuadrado A; Instituto de Investigaciones Biomédicas 'Alberto Sols' UAM-CSIC, Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III (ISCIII), 28031 Madrid, Spain., Casas AI; Pharmacology and Personalised Medicine, Maastricht University, 6211 LK Maastricht, The Netherlands.; Neurology Clinic, University Hospital Essen, 45147 Essen, Germany.; Center for Translational Neuro- and Behavioral Sciences (C-TNBS), 45147 Essen, Germany.; Department of Neurology, University Hospital Essen, 45147 Essen, Germany., Romero A; Department of Pharmacology and Toxicology, Faculty of Veterinary Medicine, Complutense University of Madrid, 28040 Madrid, Spain., Egea J; Unidad de Investigación, Hospital Santa Cristina, Instituto de Investigación Sanitaria Princesa (IIS-IP), 28006 Madrid, Spain. |
| Abstrakt: |
The role of inflammation and immunity in the pathomechanism of neurodegenerative diseases has become increasingly relevant within the past few years. In this context, the NOD-like receptor protein 3 (NLRP3) inflammasome plays a crucial role in the activation of inflammatory responses by promoting the maturation and secretion of pro-inflammatory cytokines such as interleukin-1β and interleukin-18. We hypothesized that the interplay between nuclear factor erythroid 2-related factor 2 (Nrf2) and NADPH oxidase 4 (NOX4) may play a critical role in the activation of the NLRP3 inflammasome and subsequent inflammatory responses. After priming mixed glial cultures with lipopolysaccharide (LPS), cells were stimulated with ATP, showing a significant reduction of IL1-β release in NOX4 and Nrf2 KO mice. Importantly, NOX4 inhibition using GKT136901 also reduced IL-1β release, as in NOX4 KO mixed glial cultures. Moreover, we measured NOX4 and NLRP3 expression in wild-type mixed glial cultures following LPS treatment, observing that both increased after TLR4 activation, while 24 h treatment with tert-butylhydroquinone, a potent Nrf2 inducer, significantly reduced NLRP3 expression. LPS administration resulted in significant cognitive impairment compared to the control group. Indeed, LPS also modified the expression of NLRP3 and NOX4 in mouse hippocampus. However, mice treated with GKT136901 after LPS impairment showed a significantly improved discrimination index and recovered the expression of inflammatory genes to normal levels compared with wild-type animals. Hence, we here validate NOX4 as a key player in NLRP3 inflammasome activation, suggesting NOX4 pharmacological inhibition as a potent therapeutic approach in neurodegenerative diseases. |
