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

Brain Behav Immun. 2014 Oct;41:90-100. doi: 10.1016/j.bbi.2014.04.007. Epub 2014 May 22.


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.

Keywords: Chronic unpredictable mild stress; Depression; IL-1β-related CNS inflammation; NLRP3 inflammasome; Prefrontal cortex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • 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