Nod-like receptor pyrin containing 3 (NLRP3) in the post-mortem frontal cortex from patients with bipolar disorder: A potential mediator between mitochondria and immune-activation |
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| Institution: | 1. Departments of Psychiatry and Pharmacology, 1 King''s College Circle, University of Toronto, Toronto, ON M5S 1A8, Canada;2. Center for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada;1. Integrated Research and Treatment Center (IFB) AdiposityDiseases, Leipzig, Germany;2. Center for Pediatric Research Leipzig, University Hospital for Children & Adolescents, Leipzig, Germany;3. Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Germany;4. Department of Psychiatry, University of Tasmania, Hobart, Tasmania, Australia;5. Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany;1. Laboratori de Neurofarmacologia, IUNICS/IdISPa, Universitat de les Illes Balears (UIB), Palma de Mallorca, Spain;2. Redes Temáticas de Investigación Cooperativa en Salud–Red de Trastornos Adictivos (RETICS-RTA), ISCIII, Madrid, Spain;1. Department of Pharmacology, University of the Basque Country (UPV/EHU), Spain;2. BioCruces Health Research Institute, Spain;3. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain;4. Laboratory of Neuropharmacology, Institut Universitari d’Investigació en Ciències de la Salut (IUNICS), University of the Balearic Islands, Spain;5. Centre Universitaire Romand de Médicine Légale-site Genève, University of Geneva, Switzerland;1. Laboratorio de Neurofarmacología, IUNICS-IdISPa, Universitat de les Illes Balears (UIB), and Redes Temáticas de Investigación Cooperativa en Salud-Red de Trastornos Adictivos (RETICS-RTA), Cra. Valldemossa km 7.5, E-07122 Palma de Mallorca, Spain;2. Departamento de Farmacología and Instituto Biocruces, Universidad del País Vasco/Euskal Herriko Unibertsitatea (UPV/EHU), and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), E-48940 Leioa, Bizkaia, Spain;3. Centre Universitaire Romand de Médecine Légale – Site Genève, University of Geneva, CH-1211 Geneva 4, Switzerland |
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| Abstract: | Mitochondrial complex I dysfunction, oxidative stress and immune-activation are consistently reported in bipolar disorder (BD). Mitochondrial production of reactive oxygen species was recently linked to activation of an inflammatory redox sensor, the nod-like receptor family pyrin domain-containing 3 (NLRP3). Upon its activation, NLRP3 recruits apoptosis-associated speck-like protein (ASC) and caspase-1 to form the NLRP3-inflamamsome, activating IL-1β. This study aimed to examine if immune-activation may be a downstream target of complex I dysfunction through the NLRP3-inflamamsome in BD. Post-mortem frontal cortex from patients with BD (N = 9), schizophrenia (N = 10), and non-psychiatric controls (N = 9) were donated from the Harvard Brain Tissue Resource Center. Levels of NLRP3, ASC and caspase-1 were measured by western blotting, ELISA and Luminex. While we found no effects of age, sex or post-mortem delay, lower levels of complex I (F2,25 = 3.46, p < 0.05) and NDUFS7, a subunit of complex I (F2,25 = 4.13, p < 0.05), were found in patients with BD. Mitochondrial NLRP3 (F2,25 = 3.86, p < 0.05) and ASC (F2,25 = 4.61, p < 0.05) levels were higher in patients with BD. However, levels of caspase 1 (F2,25 = 4.13, p < 0.05 for both), IL-1β (F2,25 = 7.05, p < 0.01), IL-6 (F2,25 = 5.48, p < 0.05), TNFα (F2,25 = 7.14, p < 0.01) and IL-10 (F2,25 = 5.02, p < 0.05) were increased in both BD and schizophrenia. These findings suggest that immune-activation in the frontal cortex may occur both in patients with BD and schizophrenia, while complex I dysfunction and NLRP3-inflammasome activation may be more specific to BD. |
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| Keywords: | NLRP3 Bipolar disorder Complex I Oxidative stress Post-mortem brain Frontal cortex |
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