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

J Psychiatr Res. 2016 Jan;72:43-50. doi: 10.1016/j.jpsychires.2015.10.015. Epub 2015 Oct 26.

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.

Keywords: Bipolar disorder; Complex I; Frontal cortex; NLRP3; Oxidative stress; Post-mortem brain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aging / metabolism
  • Bipolar Disorder / metabolism*
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / metabolism*
  • Caspase 1 / metabolism
  • Cytoskeletal Proteins / metabolism
  • Female
  • Frontal Lobe / metabolism*
  • Humans
  • Inflammasomes / metabolism
  • Interleukin-10 / metabolism
  • Interleukin-1beta / metabolism
  • Interleukin-6 / metabolism
  • Male
  • Middle Aged
  • Mitochondria / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Schizophrenia / metabolism
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • IL10 protein, human
  • IL1B protein, human
  • IL6 protein, human
  • Inflammasomes
  • Interleukin-1beta
  • Interleukin-6
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • PYCARD protein, human
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Caspase 1