ReviewThe role of inflammation and microglial activation in the pathophysiology of psychiatric disorders
Introduction
A growing body of evidence suggests that many psychiatric disorders, including major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, and autism are associated with distinct inflammatory mechanisms in the periphery and in the central nervous system (CNS). The relevance of inflammation in these conditions has been proposed by several studies, linking them with alterations in cytokines and acute-phase reactants. Risk factors for MDD and BD include medical conditions associated with chronic inflammatory and immunological alterations, such as rheumatoid arthritis, obesity and diabetes (Leboyer et al., 2012). Moreover, peripheral immune modulators have been shown to induce psychiatric symptoms in humans and in animal models (Dantzer et al., 2008, Harrison et al., 2009, Eisenberger et al., 2010, Haroon et al., 2012). Inflammation in the context of the nervous system, termed ‘neuroinflammation’, has been reported in patients with psychiatric disorders (Najjar et al., 2013), and is typically associated with microglial activation.
Microglia are CNS-resident cells that are usually the first to be activated in response to tissue damage or brain infections (Stertz et al., 2013). These small cells have several functions described, including (but not limited to): pathogen recognition, phagocytosis, antigen presentation, and synapse remodeling (reviewed in Boche et al., 2013). Non-activated microglia termed “quiescent” or “resting” microglia are constantly surveilling the surrounding environment in non-pathological conditions (Nimmerjahn et al., 2005, Marshall et al., 2013). In response to changes in the environment, microglial cells can be activated by changing their morphology and function (Marshall et al., 2013). Their activators include a range of different molecules, such as the P2X7purinergic receptor (P2X7R), and endogenous constituents that are normally released from injured cells, including adenosine 5′-triphosphate (ATP), S100 molecules, histones and heat shock protein (HSP), which are known as damage-associated molecular patterns (DAMPs) (Lu et al., 2014, Wiersinga et al., 2014). Specifically, P2X7R acts as a “sensor of danger” by responding to the so-called “danger signal” ATP, which is released from injured cells and activates microglia (Weisman et al., 2012, Gubert et al., 2013). The same goes for other DAMPs with their specific receptors.
Microglial activation can be divided into two distinct types: a classical M1 and an alternative M2 activation. In the M1 activation, microglial cells may become hyper-ramified or ameboid/phagocytic (Boche et al., 2013), and may synthesize proinflammatory molecules (interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6, among others), superoxide radicals, glutamate (Barger et al., 2007, Takaki et al., 2012), nitric oxide (NO) and ultimately clear infections and repair tissues. Alternatively, M2 activation, which can be triggered by cytokines such as IL-4, IL-13 or IL-25 (Boche et al., 2013, Maiorino et al., 2013), has been associated with a release of anti-inflammatory cytokines such as IL-10, insulin-growth factor-1(IGF-1), transforming growth factor-β (TGF-β), and neurotrophic factors (Ekdahl, 2012, Boche et al., 2013, Hu et al., 2015), which facilitate healing and limit neuronal injury (Najjar et al., 2013). The nature and the magnitude of the injury, along with several other factors, can influence the development of these distinct microglial phenotypes (Marshall et al., 2013). In addition to this dichotomous phenotype classification, a graded level of microglia activation has also been proposed, in which cells can go from a resting stage, to an alert, homing, phagocytic stage and finally to bystander activation, which can be differentiated by morphological features and the levels of cytokines and growth factors secreted (Raivich et al., 1999). Most importantly, identifying activated microglia in a pathological condition, although being a marker of inflammation, does not allow for an understanding of the inflammatory process. Thus, only by determining the phenotype of microglia can one identify its role in cytotoxicity and/or neuroprotection (Colton and Wilcock, 2010, Graeber et al., 2011, Marshall et al., 2013).
Several studies in the past year speculated that alterations in the number and/or morphology of microglial cells are involved in cognitive and behavioral changes observed in psychiatry disorders (Di Benedetto and Rupprecht, 2013, Müller et al., 2015, Nakagawa and Chiba, 2014, Watkins et al., 2014, Zeidan-Chulia et al., 2014, Najjar and Pearlman, 2015). However, although activation of microglia is a typical hallmark of brain pathology, the extent to which it has beneficial or detrimental functions in the brain in different psychiatric disorders remains to be elucidated (Dheen et al., 2007). Specifically, given that microglia can be activated in either a cytotoxic or a neuroprotective way, characteristics of the microglial activation assessed in a specific condition need to be taken into account. This review article aims to summarize evidence of inflammation and in major psychiatric disorders, such as major depression, BD, schizophrenia, and autism, including the role it plays in their progression and therapeutics. More specifically, the role of microglial activation and polarization, as well as associated molecular cascades, will also be discussed as a means by which these neuroinflammatory mechanisms take place, when appropriate.
Section snippets
The role of microglia in stress and depression
MDD is considered a critical public health problem, and it is estimated that approximately 350 million individuals are affected worldwide (WHO, 2012). In addition, almost 1 million lives are lost yearly due to suicide, which translates to 3000 suicide deaths every day (WHO, 2012). Until recently, the monoaminergic hypothesis appeared to be the most widely accepted theory for depression. However, a series of new studies have shown that other pathways involved with neuroplasticity or
The role of microglia in BD
BD is a severe mood disorder characterized by recurrent episodes of mania followed by depression. Although the clinical characteristic for the diagnosis of BD is the presence of manic symptoms, depression represents the predominant mood state in patients with BD type I and BD type II. The pathophysiology of BD has been attributed to deficits in monoamine neurotransmitters, such as dopamine. However, the neurobiology of BD, as well as the mechanism of action of mood stabilizers used to treat BD,
Microglial hypothesis of schizophrenia
Schizophrenia is a chronic and debilitating disorder that affects 0.5–1% of the world population (Tandon et al., 2008). Patients with this disorder present positive and negative symptoms. Positive symptoms are characterized by extra feelings or behaviors, such as hallucinations and delusions. On the other hand, negative symptoms are associated with lack of behaviors, for example, apathy and loss of interest in everyday activities. Evidence suggests that the dopamine dysfunction hypothesis,
Microglial activation in autism
The autism spectrum disorders (ASD) are neurodevelopmental disorders, which are characterized by language and intelligence deficits, as well as impairment in social interactions (Abrahams and Geschwind, 2008, Theoharides et al., 2013). Recent studies have demonstrated a relationship between autism and inflammation dysregulation/alteration (Young et al., 2011, Theoharides et al., 2013). Microglial activation has also been reported in patients with ASD. For instance, Tetreault et al. (2012)
Conclusion
Microglial activation and neuroinflammation are evident in psychiatric conditions and have been reported by preclinical and clinical studies. However, the pathological mechanisms involved in the microglial dysfunction are still not fully elucidated. Of note, it remains unclear whether microglia activation can lead to the onset of psychiatric disorders and consequently to a neuroinflammatory process. More specifically, even though microglial activation can present two opposite phenotypes, the
Acknowledgments
Laboratory of Neurosciences (Brazil) is a center within the National Institute for Translational Medicine (INCT-TM) and a member of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). This research was supported by grants from CNPq (J.Q., T.B., F.K. and G.Z.R.), FAPESC (J.Q. and T.B.), Instituto Cérebro e Mente, UNESC (J.Q.), and ĹOréal/UNESCO/ABC Brazil Fellowship for Women in Science 2011 (G.Z.R.). J.Q., T.B. and F.K. are CNPq Research Fellows. Center for
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