Microglial NLRP3 inflammasome activation mediates IL-1β-related inflammation in prefrontal cortex of depressive rats.

Abstract

Depression is an inflammatory disorder. Pro-inflammatory cytokine interleukin-1 beta (IL-1β) may play a pivotal role in the central nervous system (CNS) inflammation of depression. Here, we investigated IL-1β alteration in serum, cerebrospinal fluid (CSF) and prefrontal cortex (PFC) of chronic unpredictable mild stress (CUMS)-exposed rats, a well-documented model of depression, and further explored the molecular mechanism by which CUMS procedure induced IL-1β-related CNS inflammation. We showed that 12-week CUMS procedure remarkably increased PFC IL-1β mRNA and protein levels in depressive-like behavior of rats, without significant alteration of serum and CSF IL-1β levels. We found that CUMS procedure significantly caused PFC nuclear factor kappa B (NF-κB) inflammatory pathway activation in rats. The intriguing finding in this study was the induced activation of nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome with the increased IL-1β maturation in PFC of CUMS rats, suggesting a new grade of regulatory mechanism for IL-1β-related CNS inflammation. Moreover, microglial activation and astrocytic function impairment were observed in PFC of CUMS rats. The increased co-location of NLRP3 and ionized calcium binding adaptor molecule 1 (Iba1) protein expression supported that microglia in glial cells was the primary contributor for CUMS-induced PFC NLRP3 inflammasome activation in rats. These alterations in CUMS rats were restored by chronic treatment of the antidepressant fluoxetine, indicating that fluoxetine-mediated rat PFC IL-1β reduction involves both transcriptional and post-transcriptional regulatory mechanisms. These findings provide in vivo evidence that microglial NLRP3 inflammasome activation is a mediator of IL-1β-related CNS inflammation during chronic stress, and suggest a new therapeutic target for the prevention and treatment of depression.

• Authors: Ying Pan, Xu-Yang Chen, Qing-Yu Zhang, Ling-Dong Kong
• Journal: Brain, behavior, and immunity (Brain Behav Immun) Vol. 41 Pg. 90-100 (Oct 2014) ISSN: 1090-2139 [Electronic] Netherlands
• PMID: 24859041 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Aif1 protein, rat
• Antidepressive Agents
• Calcium-Binding Proteins
• Carrier Proteins
• IL1B protein, rat
• Inflammasomes
• Interleukin-1beta
• Microfilament Proteins
• NF-kappa B
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nerve Tissue Proteins
• Nlrp3 protein, rat
• Receptors, Cytoplasmic and Nuclear
• Fluoxetine
• Sucrose

Topics

• Anhedonia
• Animals
• Antidepressive Agents (therapeutic use)
• Calcium-Binding Proteins (analysis)
• Carrier Proteins
• Chronic Disease
• Depressive Disorder (drug therapy, metabolism, pathology)
• Drinking Behavior
• Enzyme Activation
• Fluoxetine (therapeutic use)
• Gene Expression Regulation
• Inflammasomes (physiology)
• Inflammation
• Interleukin-1beta (biosynthesis, blood, cerebrospinal fluid, physiology)
• Male
• Microfilament Proteins (analysis)
• Microglia (metabolism, pathology)
• NF-kappa B (metabolism)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nerve Tissue Proteins (analysis, biosynthesis, physiology)
• Prefrontal Cortex (metabolism, pathology)
• Random Allocation
• Rats
• Rats, Wistar
• Receptors, Cytoplasmic and Nuclear (analysis, biosynthesis, physiology)
• Stress, Physiological
• Sucrose