Functions of connexins and large pore channels on microglial cells: The gates to environment
ABSTRACT Microglial cells are not only sensitive indicators for pathology of the central nervous system (CNS), they are a key factor for neurotoxicity and degeneration in many diseases. Neuronal damage leads to reactive gliosis and to activation of microglia including cytoarchitectonic changes accompanied by alterations in surface receptor and channel expression. In this context, the release of neuroactive soluble factors like pro-inflammatory cytokines can result in increased cellular motility and a higher grade of phagocytotic activity. Ligands including glutamate, tumor necrosis factor alpha (TNF-α), cytokines, superoxide radicals and neurotrophins released by microglia have in turn effects on neuronal function and cell death. The current review focuses on large pore and hemichannel function in microglial cells under different conditions of activation and elucidates the role of these channels in cytokine release, as well as putative targets for clinical intervention in case of inflammatory processes. This article is part of a Special Issue entitled Electrical Synapses.
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- "Consistently, non-vesicular secretory mechanisms in microglia have been indicated as putative gates for excessive transmitter release in pathological conditions, as in the case of neurotoxic glutamate release through connexin hemichannels in the Rett syndrome (Maezawa and Jin, 2010). While recent reviews have comprehensively described alterations of non-vesicular secretory paths in relation to the activation state of microglia and have proposed non secretory mechanisms as putative targets for clinical intervention in brain diseases (Kielian, 2008; Mika and Prochnow, 2012), vesicular secretory pathways operating in microglia have been poorly investigated and reviewed. Hence, we here focus on emerging evidence indicating the coexistence in microglia of both classical, regulated secretion, and unconventional vesicular secretory mechanisms, the latter consisting in the release of extracellular membrane microvesicles (EMVs). "
ABSTRACT: Emerging evidence indicates that activation of microglia, the immune cells of the brain, is strictly associated to both secretion of soluble molecules and release of extracellular membrane vesicles (EMVs) into the pericellular space. Through these processes, microglia heavily influence brain cell functions, either propagating inflammation and causing damage to neurons or playing a supportive, neuroprotective role. In this review, we highlight the emerging concepts related to vesicular mechanisms of secretion operating in microglial cells, with the aim of dissecting how microglia communicate with other cell types within the brain microenvironment in health and disease.Glia 07/2013; 61(7). DOI:10.1002/glia.22497
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ABSTRACT: Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a lysosomal storage disease caused by an autosomal recessive mutation in CLN3. Regions of microglial activation precede and predict areas of neuronal loss in JNCL; however, the functional role of activated microglia remains to be defined. The inflammasome is a key molecular pathway for activating pro-IL-1β in microglia, and IL-1β is elevated in the brains of JNCL patients and can induce neuronal cell death. Here we utilized primary microglia isolated from CLN3(Δex7/8) mutant and wild type (WT) mice to examine the impact of CLN3 mutation on microglial activation and inflammasome function. Treatment with neuronal lysates and ceramide, a lipid intermediate elevated in JNCL brain, led to inflammasome activation and IL-1β release in CLN3(Δex7/8) microglia but not WT cells, as well as increased expression of additional proinflammatory mediators. Similar effects were observed following either TNF-α or IL-1β treatment, suggesting that CLN3(Δex7/8) microglia exist in primed state and hyper-respond to several inflammatory stimuli compared to WT cells. CLN3(Δex7/8) microglia displayed constitutive caspase-1 activity that when blocked led to increased glutamate release that coincided with hemichannel opening. Conditioned medium from activated CLN3(Δex7/8) or WT microglia induced significant cell death in CLN3(Δex7/8) but not WT neurons, demonstrating that intrinsically diseased CLN3(Δex7/8) neurons are less equipped to withstand cytotoxic insults generated by activated microglia. Collectively, aberrant microglial activation may contribute to the pathological chain of events leading to neurodegeneration during later stages of JNCL. This article is protected by copyright. All rights reserved.Journal of Neurochemistry 08/2013; DOI:10.1111/jnc.12385
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ABSTRACT: The coordination of tissue function is mediated by gap junctions (GJs) that enable direct cell-cell transfer of metabolic and electric signals. GJs are formed by connexins of which Cx43 is most widespread in the human body. In the brain, Cx43 GJs are mostly found in astroglia where they coordinate the propagation of Ca(2+) waves, spatial K(+) buffering, and distribution of glucose. Beyond its role in direct intercellular communication, Cx43 also forms unapposed, non-junctional hemichannels in the plasma membrane of glial cells. These allow the passage of several neuro- and gliotransmitters that may, combined with downstream paracrine signaling, complement direct GJ communication among glial cells and sustain glial-neuronal signaling. Mutations in the GJA1 gene encoding Cx43 have been identified in a rare, mostly autosomal dominant syndrome called oculodentodigital dysplasia (ODDD). ODDD patients display a pleiotropic phenotype reflected by eye, hand, teeth, and foot abnormalities, as well as craniofacial and bone malformations. Remarkably, neurological symptoms such as dysarthria, neurogenic bladder (manifested as urinary incontinence), spasticity or muscle weakness, ataxia, and epilepsy are other prominent features observed in ODDD patients. Over 10 mutations detected in patients diagnosed with neurological disorders are associated with altered functionality of Cx43 GJs/hemichannels, but the link between ODDD-related abnormal channel activities and neurologic phenotype is still elusive. Here, we present an overview on the nature of the mutants conveying structural and functional changes of Cx43 channels and discuss available evidence for aberrant Cx43 GJ and hemichannel function. In a final step, we examine the possibilities of how channel dysfunction may lead to some of the neurological manifestations of ODDD.Frontiers in Pharmacology 09/2013; 4:120. DOI:10.3389/fphar.2013.00120