Review ArticleNLRP3 inflammasome-driven pathways in depression: Clinical and preclinical findings
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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