Elsevier

Brain, Behavior, and Immunity

Volume 64, August 2017, Pages 367-383
Brain, Behavior, and Immunity

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

https://doi.org/10.1016/j.bbi.2017.03.002Get rights and content

Highlights

  • Chronic stress activates NLRP3 complex in rodent brain.

  • NLRP3 is activated in peripheral blood mononuclear cells of patients with MDD.

  • Antidepressant compounds decrease NLRP3 activation.

  • Increased IL-1β and IL-18 are frequently associated with depressive symptoms.

Abstract

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.

Section snippets

Inflammatory processes in major depressive disorder (MDD): a critical overview

Major depressive disorder (MDD) is a highly pervasive psychiatric condition, and nearly 350 million people are affected worldwide (Murray et al., 2013). Despite the significant social burden that stems from this disease, there are still significant gaps in our scientific understanding of the genesis and progression of MDD. The current diagnostic systems do not adequately reflect the relevant neurobiological alterations that drive the modified behavioral patterns found in patients (Insel et al.,

Pattern recognition receptors (PRRs)

Pattern recognition receptors (PRRs) also seem to play a major role in the reciprocal interaction between inflammatory responses and behavior. In the CNS, PRRs are primarily expressed by microglia, astrocytes, oligodendrocytes, and neurons as membrane-bound receptors (TLRs) or as cytosolic receptors (Nod-like receptors, NLRs) (Kigerl et al., 2014). These receptors act through recognition of both foreign molecules and associated cell damage and are activated by pathogen-associated molecular

Inflammasome subtypes in the CNS

The NLRs comprise a class of cytosolic sensors that can respond to a variety of DAMPs and PAMPs, which enables the activation of the inflammasome complex (Gurung et al., 2014, Halle et al., 2008, Walsh et al., 2014). Since their discovery, several different inflammasome subtypes have been described. The increasing recognition of the complexity and functions of the inflammasome complexes indicated the considerable interest in their role in the etiology and progression of brain disorders. Indeed,

Antidepressant compounds as NLRP3 modulators

The involvement of NLRP3 modulation in the antidepressant response was first tested with fluoxetine in a 12-week chronic unpredictable mild stress protocol in rats. Both the behavioral and neurochemical effects induced by stress, including NLRP3 activation were reduced by chronic fluoxetine treatment (Pan et al., 2014). Indeed, the association between the antidepressant effects of fluoxetine and its suppressive effects on the NLRP3 complex in the hippocampus and peripheral macrophages was

Inflammasome-mediated cytokines in chronic stress and MDD

IL-1β and IL-18 are the main cytokines controlled by NLRP3 inflammasome activation. They are members of the IL-1 family, which comprises IL-1α, IL-1β, IL-1 receptor antagonist (IL-1Ra), IL-18, IL-33, and IL-1F5–IL-1F10 (Dinarello, 2000, Dinarello, 2010, Sims and Smith, 2010). These cytokines are involved in a variety of immune responses and the initiation, regulation, and maintenance of inflammation (Dinarello, 2000). IL-1β and IL-18 have pro-domains that require cleavage by the NLRP3

Conclusions and perspectives

In this review, we summarized the current knowledge regarding the involvement of the NLRP3 inflammasome complex in chronic stress models and patients with MDD. It is evident that relying solely on subjective symptoms for MDD diagnosis and assessment of treatment efficacy is ineffective, and the establishment of clinically relevant, objective measurements that could be used as biomarkers is urgently needed. Although the impact of immune dysfunction on psychiatric disorders has been explored in

Disclosure and Funding

All the authors declare no conflict of interests. This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES) Brazil and L’Óreal, UNESCO and Brazilian Academy of Sciences. MPK and ALSR are CNPq Research Fellows. HP received support from Comisión Sectorial de Investigación Científica (CSIC-UDELAR), Uruguay, Agencia Nacional de Investigación e Innovación (ANII), Uruguay, PEDECIBA, Uruguay,

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