Over the past three decades, an intricate interaction between immune activation, release of pro-inflammatory cytokines and changes in brain circuits related to mood and behavior has been described. Despite extensive efforts, questions regarding when inflammation becomes detrimental or how we can target the immune system to develop new therapeutic strategies for the treatment of psychiatric disorders remain unresolved. In this context, novel aspects of the neuroinflammatory process activated in response to stressful challenges have recently been documented in major depressive disorder (MDD). The Nod-like receptor pyrin containing 3 inflammasome (NLRP3) is an intracellular multiprotein complex responsible for a number of innate immune processes associated with infection, inflammation and autoimmunity. Recent data have demonstrated that NLRP3 activation appears to bridge the gap between immune activation and metabolic danger signals or stress exposure, which are key factors in the pathogenesis of psychiatric disorders. In this review, we discuss both preclinical and clinical evidence that links the assembly of the NLRP3 complex and the subsequent proteolysis and release of the pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) in chronic stress models and patients with MDD. Importantly, we also focus on the therapeutic potential of targeting the NLRP3 inflammasome complex to improve stress resilience and depressive symptoms.

NLRP3 inflammasome-driven pathways in depression: Clinical and preclinical findings.

Abstract Major depressive disorder is a highly debilitating psychiatric disorder involving the dysfunction of different cell types in the brain. Microglia are the predominant resident immune cells in the brain and exhibit a critical role in depression. Recent studies have suggested that depression can be regarded as a microglial disease. Microglia regulate inflammation, synaptic plasticity, and the formation of neural networks, all of which affect depression. In this review, we highlighted the role of microglia in the pathology of depression. First, we described microglial activation in animal models and clinically depressed patients. Second, we emphasized the possible mechanisms by which microglia recognize depression-associated stress and regulate conditions. Third, we described how antidepressants (clinical medicines and natural products) affect microglial activation. Thus, this review aimed to objectively analyze the role of microglia in depression and focus on potential antidepressants. These data suggested that regulation of microglial actions might be a novel therapeutic strategy to counteract the adverse effects of devastating mental disorders. 

/pdf/microglia-in-depression-an-overview-of-microglia-in-the-jv7oce0f.pdf

Microglia in depression: an overview of microglia in the pathogenesis and treatment of depression

Endoplasmic reticulum stress (ERS) is a protective response to restore protein homeostasis by activating the unfolded protein response (UPR). However, UPR can trigger cell death under severe and/or persistently high ERS. The NLRP3 inflammasome is a complex of multiple proteins that activates the secretion of the proinflammatory cytokine IL-1β in a caspase-1-dependent manner to participate in the regulation of inflammation. The NLRP3 inflammasome involvement in ERS-induced inflammation has not been completely described. The intersection of ERS with multiple inflammatory pathways can initiate and aggravate chronic diseases. Accumulating evidence suggests that ERS-induced activation of NLRP3 inflammasome is the pathological basis of various inflammatory diseases. In this review, we have discussed the networks between ERS and NLRP3 inflammasome, with the view to identifying novel therapeutic targets in inflammatory diseases. KEY POINTS: • Endoplasmic reticulum stress (ERS) is an important factor for the activation of the NLRP3 inflammasomes that results in pathological processes. • ERS can activate the NLRP3 inflammasome to induce inflammatory responses via oxidative stress, calcium homeostasis, and NF-κB activation. • The interactions between ERS and NLRP3 inflammasome are associated with inflammation, which represent a potential therapeutic opportunity of inflammatory diseases.

Crosstalk between ER stress, NLRP3 inflammasome, and inflammation

Depression has been widely accepted as a major psychiatric disease affecting nearly 350 million people worldwide. Research focus is now shifting from studying the extrinsic and social factors of depression to the underlying molecular causes. Microglial activity is shown to be associated with pathological conditions, such as psychological stress, pathological aging, and chronic infections. These are primary immune effector cells in the CNS and regulate the extensive dialogue between the nervous and the immune systems in response to different immunological, physiological and psychological stressors. Studies have suggested that during stress and pathologies, microglia play a significant role in the disruption of neuroplasticity and have detrimental effects on neuroprotection causing neuroinflammation and exacerbation of depression. After a systematic search of literature databases, relevant articles on the microglial regulation of bidirectional neuroimmune pathways affecting neuroplasticity and leading to depression were reviewed. Although several hypotheses have been proposed for the microglial role in the onset of depression, it is clear that all molecular pathways to depression are linked through microglia-associated neuroinflammation and hippocampal degeneration. Molecular factors such as an excess of glucocorticoids and changes in gene expression of neurotrophic factors, as well as neuro active substances secreted by gut microbiota have also been shown to affect microglial morphology and phenotype resulting in depression. This review aims to critically analyze the various molecular pathways associated with the microglial role in depression.

/pdf/microglia-an-interface-between-the-loss-of-neuroplasticity-2mrhukoeuv.pdf

Microglia: An Interface between the Loss of Neuroplasticity and Depression.

Antidepressants induce autophagy dependent-NLRP3-inflammasome inhibition in Major depressive disorder

Background: Emerging evidence indicates that NLRP3 inflammasome-induced inflammation plays a crucial role in the pathogenesis of depression. Thus, inhibition of NLRP3 inflammasome activation may offer a therapeutic benefit in the treatment of depression. Fluoxetine, a widely used antidepressant, has been shown to have potential antiinflammatory activity, but the underlying mechanisms remain obscure.

Methods: We used a chronic mild stress model and cultured primary macrophage/microglia to investigate the effects of fluoxetine on NLRP3 inflammasome and its underlying mechanisms.

Results: We demonstrated that fluoxetine significantly suppressed NLRP3 inflammasome activation, subsequent caspase-1 cleavage, and interleukin-1β secretion in both peripheral macrophages and central microglia. We further found that ﬂuoxetine reduced reactive oxygen species production, attenuated the phosphorylation of double-stranded RNA-dependent protein kinase, and inhibited the association of protein kinase with NLRP3. These data indicate that fluoxetine inhibits the activation of NLRP3 inflammasome via downregulating reactive oxygen species-protein kinase-NLRP3 signaling pathway. Correspondingly, in vivo data showed that fluoxetine also suppressed NLRP3 inflammasome activation in hippocampus and macrophages of chronic mild stress mice and alleviated chronic mild stress-induced depression-like behavior.

Conclusions: Our findings reveal that fluoxetine confers an antidepressant effect partly through inhibition of peripheral and central NLRP3 inflammasome activation and suggest the potential clinical use of fluoxetine in NLRP3 inflammasome-driven inflammatory diseases such as depression.

/pdf/fluoxetine-inhibits-nlrp3-inflammasome-activation-4za114yvmd.pdf

Fluoxetine Inhibits NLRP3 Inflammasome Activation: Implication in Depression.

ATP-sensitive potassium (K-ATP) channels couple cellular metabolism to electric activity. Although Kir6.2-composed K-ATP channel (Kir6.2/K-ATP channel) has been demonstrated to regulate inflammation, a common cause of most liver diseases, its role in liver injury remains elusive. Kir6.2 knockout mice were used to prepared LPS-induced liver injury model so as to investigate the role of Kir6.2/K-ATP channels in the injury. Histochemistry was applied to evaluate the extent of liver injury. Proinflammatory cytokines were analyzed by ELISA. Endoplasmic reticulum (ER) stress and autophagy were assessed by western blotting. We showed that Kir6.2 knockout markedly promoted the infiltration of lymphocytes and neutrophils in liver and significantly elevated serum levels of alanine transaminase (ALT) in respond to LPS treatment. We further found that Kir6.2 deficiency enhanced the activation of NF-κB and NLRP3 inflammasome following LPS challenge, and thereby increased the levels of pro-inflammatory cytokines IL-1β, IL-18 and TNF-α. Treatment of wild-type mice with the K-ATP channel opener iptakalim (IPT) could protect against LPS-induced liver injury through attenuating NLRP3 inflammasome-mediated inflammatory responses. Furthermore, Kir6.2 knockout-induced activation of NLRP3 inflammasome aggravated endoplasmic reticulum (ER) stress, autophagy and subsequent hepatocyte death. Kir6.2 deficiency exacerbated LPS-induced liver injury by enhancing NLRP3 inflammasome-mediated inflammatory response. Thus, Kir6.2/K-ATP channel may be a potential candidate target for the treatment and prevention of liver injury.

Kir6.2 knockout aggravates lipopolysaccharide-induced mouse liver injury via enhancing NLRP3 inflammasome activation.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

Jun Tan

Author Tools

Chat about Author

Papers

Fluoxetine Inhibits NLRP3 Inflammasome Activation: Implication in Depression.

Kir6.2 knockout aggravates lipopolysaccharide-induced mouse liver injury via enhancing NLRP3 inflammasome activation.