title: 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.
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-inflammasome, activating IL-1β. This study aimed to examine if immune-activation may be a downstream target of complex I dysfunction through the NLRP3-inflammasome 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.
authors.affiliation: Departments of Psychiatry and Pharmacology, 1 King's College Circle, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: helenakim0913@gmail.com.
authors.forename: Helena Kyunghee
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Departments of Psychiatry and Pharmacology, 1 King's College Circle, University of Toronto, Toronto, ON M5S 1A8, Canada; Center for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada. Electronic address: ana.andreazza@utoronto.ca.
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Andreazza
authors.affiliation: Departments of Psychiatry and Pharmacology, 1 King's College Circle, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: nikaelmi@gmail.com.
authors.forename: Nika
authors.initials: N
authors.lastname: Elmi
authors.affiliation: Departments of Psychiatry and Pharmacology, 1 King's College Circle, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: wenjun.chen@mail.utoronto.ca.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Chen
authors.affiliation: Departments of Psychiatry and Pharmacology, 1 King's College Circle, University of Toronto, Toronto, ON M5S 1A8, Canada; Center for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada. Electronic address: ltrevor.young@utoronto.ca.
authors.forename: L Trevor
authors.initials: LT
authors.lastname: Young
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism; D001714:Bipolar Disorder / Q000378:metabolism*; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D012559:Schizophrenia / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C508609:IL10 protein, human; C508585:IL1B protein, human; C508600:IL6 protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D020170:Caspase 1
keywords: Bipolar disorder; Complex I; Frontal cortex; NLRP3; Oxidative stress; Post-mortem brain