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Review
. 2015 Dec 17:9:476.
doi: 10.3389/fncel.2015.00476. eCollection 2015.

Neuroinflammation and Depression: Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation

Dora Brites  1 , Adelaide Fernandes  1
Affiliations
Review

Neuroinflammation and Depression: Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation

Dora Brites et al. Front Cell Neurosci. .

Abstract

Patients with chronic inflammation are often associated with the emergence of depression symptoms, while diagnosed depressed patients show increased levels of circulating cytokines. Further studies revealed the activation of the brain immune cell microglia in depressed patients with a greater magnitude in individuals that committed suicide, indicating a crucial role for neuroinflammation in depression brain pathogenesis. Rapid advances in the understanding of microglial and astrocytic neurobiology were obtained in the past 15-20 years. Indeed, recent data reveal that microglia play an important role in managing neuronal cell death, neurogenesis, and synaptic interactions, besides their involvement in immune-response generating cytokines. The communication between microglia and neurons is essential to synchronize these diverse functions with brain activity. Evidence is accumulating that secreted extracellular vesicles (EVs), comprising ectosomes and exosomes with a size ranging from 0.1-1 μm, are key players in intercellular signaling. These EVs may carry specific proteins, mRNAs and microRNAs (miRNAs). Transfer of exosomes to neurons was shown to be mediated by oligodendrocytes, microglia and astrocytes that may either be supportive to neurons, or instead disseminate the disease. Interestingly, several recent reports have identified changes in miRNAs in depressed patients, which _target not only crucial pathways associated with synaptic plasticity, learning and memory but also the production of neurotrophic factors and immune cell modulation. In this article, we discuss the role of neuroinflammation in the emergence of depression, namely dynamic alterations in the status of microglia response to stimulation, and how their activation phenotypes may have an etiological role in neurodegeneneration, in particular in depressive-like behavior. We will overview the involvement of miRNAs, exosomes, ectosomes and microglia in regulating critical pathways associated with depression and how they may contribute to other brain disorders including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD), which share several neuroinflammatory-associated processes. Specific reference will be made to EVs as potential biomarkers and disease monitoring approaches, focusing on their potentialities as drug delivery vehicles, and on putative therapeutic strategies using autologous exosome-based delivery systems to treat neurodegenerative and psychiatric disorders.

Keywords: astrocytes; ectosomes; exosomes; glia interplay; microRNAs; microglia; neurodegeneration; oligodendrocytes.

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Figures

Figure 1
Figure 1
Microglia activation with release of extracellular vesicles (EVs). In the healthy central nervous system, microglia have highly ramified morphology with thin processes, which constantly monitor brain parenchyma to maintain the homeostasis. These microglia are commonly designated as surveillant microglia. Upon stimuli, namely by the proinflammatory lipopolysaccharide (LPS), reactive or activated microglia acquire different morphologies from hypertrophic with enlarged processes to an amoeboid shape. Intracellularly, several pathways become activated including the mitogen-activated protein kinases (MAPKs) superfamily, comprising the c-Jun N-terminal kinase (JNK 1/2) and p38 proteins, which will trigger the activation of the nuclear factor-κB (NF-κB) and consequent induction of first-line cytokine production, such as interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α. In parallel, microglia are also able to sense cellular/molecular debris and intervene by phagocytosing them. Interestingly, messenger RNAs (mRNAs, curved symbols), microRNAs (miRNAs, black symbols) and cytokines (diamond-like symbols) are selectively incorporated into multivesicular bodies (MVBs) and may be released from activated microglia encapsulated in EVs, comprising exosomes and microvesicles. While exosomes are endocytic membrane-derived vesicles of small size (30–100 nm) that are contained in MVBs in the endosomal system and secreted upon MVB fusion with the plasma membrane, microvesicles/ectosomes are quite large vesicles (100–1000 nm) that bud directly from the plasma membrane. These vesicles will act as vehicles in cell-to-cell communication, being considered potential carriers of altered molecules promoting disease propagation.
Figure 2
Figure 2
Composition of typical microglial exosomes. Exosomes are packed with several cellular components including messenger RNAs (mRNAs, curved symbols), microRNAs (miRNAs, black symbols) and proteins. Microglia-derived exosomes express specific markers of late endosomes corroborating their organelle origin, as well as major histocompatibility complexes (MHCs) class II molecules and enzymes (i.e., cathepsin S) indicative of their function as antigen presenting cells, and integrins involved in antigen presentation and pattern recognition receptors important for innate immunity. Flotillin 1 is a membrane-associated protein that is enriched in exosomes and thus commonly used as an exosomal marker. Tetraspanins are a family of transmembrane proteins that become integrated in the membrane of EVs and among them are CD9, CD63 and CD81, which are particularly enriched in microglia-derived exosome. The surface-bound aminopeptidase CD13 that degrades enkephalins and the lactate transporter monocarboxylate transporter 1MCT-1 are also highly expressed in exosomes released from microglial cells. CD14 is a monocyte/macrophage marker, regularly used to characterize exosomal preparations. Extrusion of Na, K-ATPase is likewise frequent in different populations of exosomes. Microvesicles also carry the proinflammatory cytokine interleukin (IL-1β) that is shed from the plasma membrane of the microglial cell upon ATP stimulation. In addition, exosomes may additionally contain a distinct set of proteins, such as cytoskeletal proteins and the glycolytic protein glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The illustration is based on proteomic analysis of exosome preparations derived from N9 microglial cells (Potolicchio et al., 2005).
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