title: 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.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China.
authors.forename: Xu-Yang
authors.initials: XY
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China.
authors.forename: Qing-Yu
authors.initials: QY
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China. Electronic address: kongld@nju.edu.cn.
authors.forename: Ling-Dong
authors.initials: LD
authors.lastname: Kong
mesh_terms: D059445:Anhedonia; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D002135:Calcium-Binding Proteins / Q000032:analysis; D002352:Carrier Proteins; D002908:Chronic Disease; D003866:Depressive Disorder / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004327:Drinking Behavior; D004789:Enzyme Activation; D005473:Fluoxetine / Q000627:therapeutic use; D005786:Gene Expression Regulation; D058847:Inflammasomes / Q000502:physiology*; D007249:Inflammation; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000097:blood / Q000134:cerebrospinal fluid / Q000502:physiology*; D008297:Male; D008840:Microfilament Proteins / Q000032:analysis; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology*; D013312:Stress, Physiological; D013395:Sucrose
chemical_list: C100745:Aif1 protein, rat; D000928:Antidepressive Agents; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; C000594089:IL1B protein, rat; D058847:Inflammasomes; D053583:Interleukin-1beta; D008840:Microfilament Proteins; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009419:Nerve Tissue Proteins; C573346:Nlrp3 protein, rat; D018160:Receptors, Cytoplasmic and Nuclear; D005473:Fluoxetine; D013395:Sucrose
keywords: Chronic unpredictable mild stress; Depression; IL-1β-related CNS inflammation; NLRP3 inflammasome; Prefrontal cortex