Abstract
Microglia are the immunocompetent resident macrophages of the central nervous system and constitutes 15–20 % of the glial population. They provides the first line of defence against any disease or insult and display enormous structural and functional plasticity. Microglial cells are also well establised to play a very important role in the pathogenesis of various neurological disorders. Microglial activation not only protect and repair the damaged tissue by eliminating the dying cell and assisting the restorative process but are also implicated in inducing neurodegeneration. This review provides a comprehensive account of development and various physiological states of microglia and their role in healthy and disease brain.
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2.1 Introduction
Our understanding of microglia has moved from being a ‘silent’ cell in healthy brain to an actively involved component in brain physiology, neurogenesis, cognition and behavioural functions. They are the surveyors of the healthy brain with actively retracting and extending their processes and thus maintaining the pre- and post-synaptic elements and fine tuning of the neuronal circuits. Thus, a disruption of this homeostatic act of microglia becomes the prime cause of neuronal disorders. Microglia are nomadic cells of the brain that continuously survey the central nervous system (CNS) with their highly motile extensions for any kind of brain insult (Gehrmann et al. 1995) and constitute 15–20 % of the total glial population in the central nervous system (Carson et al. 2006). They are the resident macrophages of CNS and are immunocompetent phagocytic cells and constitute the first line of defence against any disease or insult and exhibit structural and functional plasticity. Microglia are considered responsible to maintain the homeostasis within the brain and undergo appropriate structural transformations to perform various immunological functions. First recognized by Nissl in 1880, later Pio-del Rio Hortega, a Spanish neuroanatomist, described microglia as resting ramified cells using silver staining methods (Del Rio-Hortega 1932).
Microglial cells are now well recognized as an elementary contributor in the pathogenesis of various neurological diseases and disorders (Heneka et al. 2010; Parpura et al. 2012; Verkhratsky et al. 2014). As affiliate of brain defence system, on any immune breaching or insult, microglia become activated (Saxena et al. 2007; Patro et al. 2010a, b, 2013; Nagayach et al. 2014a, b, 2015; Sharma et al. 2015). On activation, these immune cells get rapidly transformed into the reactive phenotype and slack their highly ramified morphology not only to protect but also to repair the damaged tissue by removing the dying cell debris and facilitating the healing process (Hanisch and Kettenmann 2007; Kettenmann et al. 2011). On the contrary, microglial activation is also responsible in aggravating the neurodegeneration (Block and Hong 2005; Venero et al. 2011). Understanding of the imperative and multitasking attribute of microglial cells, like its stature and response following neuroinflammation deserves pertinent investigation.
2.2 Physiological States of Microglia
Morphologically, microglia have three major transitional stages that can be distinguished as: amoeboid, ramified or resting and reactive or activated (Fig. 2.1) and these states perform varied functions in the brain.
Amoeboid microglia are round or irregular in shape. They are more prevalent during development, originate from the yolk sac and populate the developing brain early. Association of developmental neuronal cell death and microglia has been reported in most parts of the CNS (Pont-Lezica et al. 2011). Because of phagocytosis as well as their ability to induce apoptosis in unwanted neurons in developing brain, microglia are important participant in the process of CNS development. They also interact with the synapses and modulate synaptic plasticity via pruning of excessive unwanted synapses and this is mediated by the complement pathway (Schafer et al. 2012; Ginhoux et al. 2013; Neiva et al. 2014). Morphologically, they closely resemble the macrophages. Amoeboid microglia are generated from primitive myeloid/ haematopoietic progenitor cells during the embryonic and perinatal stage and sustain up to the early postnatal stages in rats (Prinz and Mildner 2011; Gomez et al. 2013) and finally transform into ramified microglia (Kaur et al. 1985). The development of microglia and role of microglia in brain development have been reviewed by Pont-Lezica et al. (2011) and Nayak et al. (2014).
Ramified or ‘resting surveillent microglia’ of the adult CNS consist of small cell body with short, wispy and fine processes. These processes extend into the brain microenvironment creating a matrix-like structure that helps to better perceive the CNS milieu. Yamasaki et al. (2014) have reviewed the available information on the differentiation of the resident microglia and the monocytes in neuroinflammatory states. Microglia are considered to be the critical effectors and regulators of changes in CNS homeostasis in health and disease (Prinz and Priller 2014) as well as during CNS development. Microglia even in healthy brain continuously survey the CNS for any damage or insult as shown in in vivo time-lapse video microscopy and hence they are never in a state of rest (Nayak et al. 2014). The studies of Hellwig et al. (2013) have established the active role of such cells as depletion of ramified microglia prior to experimental stroke exacerbated the damage, establishing the active and protective role of the so called ‘resting microglia’.
Reactive microglia: Following any unfavourable stimuli ramified microglia get transformed into a reactive or activated state. Such cells have thick and retracted processes with a large and irregular shaped cell body. Reactive microglia even start proliferating to ascertain better screening and support as a hallmark of microglial activation (Niquet et al. 1994). Depending upon the stimulus and progression of the diseased state, microglial activation acts in two ways; either help in efficacious restoration of the injured brain cells or generate a threatening environment that results in exaggerated brain damage. Recent studies with mouse models of neurodegenerative disorders have helped us in better understanding to an extent the role of microglia in health and disease (Hellwig et al. 2013). To overcome the confusion, the activity-dependent microglial activation spectrum (Tang and Le 2015) was developed on the basis of cytoactive factors released by the reactive microglia (Fig. 2.1). The ‘classical activation (popularly known as M1 phase)’ represents the initial innate immune response induced by Toll-like receptor (TLR) ligands and interferon-γ (IFN-γ) followed by the generation of pro-inflammatory cytokines. The reactive release of a plethora of pro-inflammatory molecules like tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), interleukin-12 (IL-12), superoxide anions, nitric oxide synthase, redox molecules like nitrogen dioxide 2 (NOX2), nitrogen dioxide1 (NOX1), a member of Rho family of GTPases (RAC1), inducible nitric oxide synthase (iNOS), nitric oxide synthase 2 (NOS2) and excitotoxic molecules like group II metabotropic glutamate receptor (MGluR2), glutamate transporter-1 (GLT-1), purinergic P2X7 receptor (P2X7-R), etc. (Benoit et al. 2008). The next alternate phase of microglial activation is ‘M2 or alternate activation’ phase, that dampen inflammation by switching over to the anti-inflammatory state by secreting molecules like interleukin-4 (IL-4), interleukin-3 (IL-13), interleukin-1 receptor antagonist (IL-1RA), scavenging receptors and extracellular matrix molecules (Luo and Chen 2012). The cytoactive molecules thus released mitigate the generation of pro-inflammatory molecules. This accelerates the process of wound healing and damaged tissue repair (Martinez et al. 2008). The third or subtype of M2 phase is ‘acquired deactivation’ associated with deactivation of glial inflammation and uptake of apoptotic cells or oxidized lipids via release of anti-inflammatory cytokines like transforming growth factor-β (TGF-β) and interleukin-10 (IL-10; Gregory and Devitt 2004; Colton 2009).
2.3 Development of Microglia
The origin of microglia and its cell lineage still remains highly controversial and debatable. Microglia arise early during development from precursor cells in the embryonic yolk sac that seed the brain rudiment and appear to persist throughout the life. Microglia are the only cell population in the CNS that originate outside the brain. The differentiation of yolk sac macrophages into typical microglia is dependent on transcription factors like IFM regulatory factor-8 (IRF-8; Ginhoux et al. 2013; Prinz and Priller 2014). Bone marrow-derived progenitors or monocytes are also considered to be recruited for supplementing the microglial population (Saijo et al. 2013; Ginhoux et al. 2013; Prinz and Priller 2014).
The neuroectodermal matrix cells and yolk sac cells are the two distinct sources of microglial precursors (Saijo and Glass 2011). Prenatally, these cells invade the brain through meninges, choroid plexus and ventricles (Boya et al. 1991; Ginhoux et al. 2010). This primeval microglial population was reported in human gestation week 5.5 near the di-telencephalic fissure (Monier et al. 2006). First, the neuroectodermal and yolk sac cells populate the brain during first two trimesters in humans and between embryonic days 10/9.5–10.5 in rodents, and grow as amoeboid microglia (Ginhoux et al. 2010). Subsequently in early days of postnatal development, the circulating monocytes developed from blood borne precursors later give rise to amoeboid microglia (Rezaie and Male 2002). The hematopoietic stem cells in developing and adult brain have also been reported to transform into microglia (Alliot et al. 1991). This has been supported by chimeric animal study following irradiation (Hickey et al. 1992) and in experimental model of allergic encephalomyelitis (EAE; Lassmann and Hickey 1993). However, as a contrast, it has also been reported that microglia also existed before brain vascularization and production of monocytes in hematopoietic tissues indicating thereby that all microglia are not hematopoietic in origin (Shepard and Zon 2000; Takahashi 2001). The perivascular microglia are the only cell population that are continuously replaced in the adulthood by bone marrow-derived haematopoietic precursors (Hickey and Kimura 1988). While we continue debating the microglial lineage and origin, interestingly two independent reports claim that microglia can themselves act like pluripotent stem cells and can also transform into astrocytes, neurons and oligodendrocytes (Yokoyama et al. 2004; Matsuda et al. 2008) although the lineage of microglia is different than the astrocytes and neurons. This is being actively investigated and remains to be established and explored.
2.4 Microglia in Healthy Brain
2.4.1 In Developing Brain
Brain development and maturation involves a continuous refinement of synapses involving pruning of inappropriate synapses and strengthening of the established ones. Microglia have been implicated as a major player for the developmental synaptic pruning (Rakic and Zecevic 2000). The activated microglia surround the regions undergoing developmental synapse turnover, and remove the unnecessary synapses (Paolicelli et al. 2011). This happens in a complement-dependent manner. During the embryonic and early postnatal life amoeboid microglia expressing DNAX associated protein 12 (DAP12), complement and fractalkine receptors are directed towards the developing synaptic sites. Such microglia engulf the complement proteins (C1q and C3) and tagged synapses (Paolicelli et al. 2011; Schafer et al. 2013). Thus, any kind of deviation in microglial involvement leads to deficits in synaptic remodelling and maintenance, resulting in developmental disorders. Microglia are also believed to be involved in regulation of neuronal differentiation (Farinas et al. 2002) and apoptosis (Miller and Kaplan 2001) by producing neurotrophins (Nakajima et al. 2001) and the presence of microglia secreted basic fibroblast growth factors (bFG; Bansal 2002) and cytokine IL-1β have been reported to enhance proliferation and differentiation of oligodendrocytes and astrocytes. Microglia undoubtedly play an authoritatively supportive and directive role in both neurogenesis and gliogenesis in developing brain (Thored et al. 2009).
2.4.2 In Adult Brain
‘Ramified/(resting?) surveillent’ microglia reside at strategic locations throughout the mammalian brain and spinal cord. Such microglia are unremittingly surveying the healthy brain for any disparaging condition at a speed of 1.47 µm s−1 with their long thin processes (Nimmerjahn et al. 2005). Recent in vivo studies have recorded the region specific speed of process motility to be between 0.2 and 6.5 µm/min (Tremblay et al. 2010). During such scrutiny microglial processes constantly establish a direct contact with neuronal synapses (Wake et al. 2009). Such microglia release various neurotrophic growth factors to promote the neuronal survival and also to enhance neurogenesis (Ekdahl et al. 2009). In neurodegenerative diseases and following brain insults the resident microglia get stimulated and transform into activated or reactive state. In such circumstances microglia release numerous inflammatory molecules, growth factors, matrix proteins, chemokines, prostanoids and reactive free radicals (Fig. 2.2) either contributing to neuronal dysfunction and cell death or to provide support in the healing process (Gomes-Leal 2012). The detrimental or beneficial role of microglia depends upon the type and intensity of the insult and associated microglia activation stature. This may even call for microgliosis. Microglia in adult brain are not evidenced to have the ability of restoring their normal density, if depleted experimentally from the pool of precursor cells dispersed all over the brain (Parkhurst et al. 2013; Elmore et al. 2014), rather than depending upon the influx from the peripheral bloodstream as reported previously (Hughes and Bergles 2014). This may be one of the mechanisms how the old and/or damaged microglia are replaced with new healthy microglia during progression of a disease and ageing conditions.
It is now clear that microglia are also important in both learning and synaptic remodelling (Parkhurst et al. 2013) and take part in activity-dependent structural remodelling both driven by sensory input and age-related factors (Wake et al. 2009; Tremblay et al. 2012). Microglia in adult brain help in regulation of long-term potentiation (LTP) and tuning of synaptic strength, which is responsible for consistent long-term neural networks (Ben Achour and Pascual 2010; Kettenmann et al. 2011). Microglia also maintain the synaptic plasticity by releasing various soluble molecules responsible for regulating learning and memory and augmentation of N-methyl-d-aspartate (NMDA)-mediated LTP responses. It has been predicted that the absence of microglia-mediated fractalkine receptor CX3CR1 signalling and secretion of glycine and L-serine by experimental intervention results in diminished learning and memory (Hayashi et al. 2006; Rogers et al. 2011). Moreover, microglia also mediate the modulation of GABAergic transmission and basal glutamatergic signalling via brain-derived neurotrophic factor (BDNF) and adenosine triphosphate (ATP; Coull et al. 2005; Pascual et al. 2012). BDNF is required for tyrosine kinase B (TrkB) phosphorylation responsible for synaptic plasticity. This has now been established in mice models depleted of microglia that have impaired ability in multiple learning tasks. Such mice also presented a reduction in motor learning-associated synaptic formation.
2.4.3 In Aged Brain
The immune components in the ageing brain are equally affected with age-associated challenges. The immune system in aged brain is also more susceptible towards age-associated damage and dysfunction (Yung and Julius 2008). Microglial dystrophy has been noted as an indication of microglial senescence in brain (Streit et al. 2004; Kushwaha 2009; Patro et al. 2010c). With advancing age, microglia become more reactive (Streit 2006; Godbout and Johnson 2009), exhibit an amoeboid-like morphology and present an upregulation of major histocompatibility complex class II antigens, toll-like receptors 4 (TLR4) and cluster of differentiation 14 (CD14) receptors on their surface. Concomitantly, microglia also express an elevated pro- (TNF-α, IL-1β, IL-6) and anti-(TGF-β, IL-10) inflammatory cytokines in the healthy senile brain of aged mice (Sierra et al. 2007; Godbout and Johnson 2009). However, it still remains to be established either such primed state is associated with the ageing changes of the brain or ageing of the microglial cells themselves.
Ageing, age-associated exposure to stress and neurodegenerative diseases, all induce a ‘priming’ stimulus to microglia. Microglial priming and impaired microglial response is suggestive of age-related changes in microglial regulation (Wynne et al. 2009). Amplified cytokine response by primed microglia has been related to the behavioural distortions like maladaptive sickness response studied in aged subjects exposed to peripheral stimulation (Dilger and Johnson 2008). Increased cytokine secretion by such ‘primed’ microglia following altered immune reaction also cause cognitive impairment in aged brain (Chen et al. 2008).
2.5 General Microglial Physiology
2.5.1 Ion Channels
Myriad of microglial patch-clamp studies in tissue slices and in cell culture showed that microglia possess various ion channels, comprising K+, Ca2+ and Na+ channels. These ion channels undoubtedly play a potential role in both regulation and maintenance of microglial functions (Färber and Kettenmann 2005, 2006a, b; Eder 2005; Schilling and Eder 2007; Black et al. 2009). In general, ion channels in all living cells may influence several cellular processes like, proliferation, migration, apoptosis, secretion and excitability, etc. via movement of cations or anions across the membrane through hydrophilic pores. The functional stature of the microglia evidently states the expression patterns of the ion channels. Expression of various cytokines or immune molecules fluctuate the pH along the gradient and/or activation of the G proteins or protein kinase C, that in turn could modulate the microglial ion channels. The functional coherence and transforming ability of microglial ion channels during various conditions make them a suitable target to study under pathophysiological process like neuroinflammation that further contributes to the onset or progression of neurological disorders.
2.5.2 Sodium Channels
In the healthy CNS (in vivo) the evidential data regarding the functional activity of voltage-operated Na+ channels in microglial cells is scanty (Black and Waxman 2012). However, in vitro study in rat microglia (Black et al. 2009) depicted the three major isoforms of sodium channels enlisted as, Nav1.1, Nav1.6 (tetrodotoxin-sensitive) and Nav1.5 (tetrodotoxin-insensitive). Reportedly, Nav1.6 is the most abundant isoform that also participate in the modification of microglial functions. In an experiment of primary cultures, mice lacking Nav1.6 express decrement in the LPS-exposed phagocytosis (Craner et al. 2005).
2.5.3 Calcium-Permeable Channels
Expression of classical voltage-operated Ca2+ channels is considered to be absent in microglia in the CNS (both in vivo and in vitro). Store-operated channels and channels of TRP family are the two main types of Ca2+ permeable channels in microglia. Similar to all other non-excitable cells, microglial cells also possess store-operated Ca2+ entry that was mediated by the Ca2+ release activated channels, i.e. TRP channels.
2.5.4 Calcium Signalling in Microglia
Calcium signalling is a homeostatic mechanism controlled by an evolutionary conserved cascade of molecules, that directs both intracellular calcium buffering and calcium transportation across the cellular membrane (Petersen et al. 2005). In resting microglial cells, calcium signalling is triggered by the calcium entry through ligand-gated plasmalemma and store-operated calcium permeable channels that further direct the release of intracellular stored calcium (Färber and Kettenmann 2006a). Microglia constitute both type of intracellular calcium channels, i.e. ryanodine receptors (RyRs) and inositol 1,4,5-trisphosphate (InsP3)-gated Ca2+ (InsP3Rs). Microglial calcium signalling is mainly initiated by InsP3Rs that further activates the G-protein-coupled metabotropic receptors connected to phospholipase C (PLC; Kettenmann et al. 2011).
2.5.5 Potassium Channels
Potassium channels (Kv) were credited as one of the first ion channels characterized in the microglia (Kettenmann et al. 1990). Precisely, the inward rectifier Kv (KIR), is the first marker channel identified as the marker of activated microglia. Potassium channels in microglia have largely been studied in cultures and/or in tissue slices. The inward rectifier K+ currents are the main source of membrane permeability in invading amoeboid microglia during perinatal brain development. Such currents become almost undetectable as the cells get transferred to their ramified surveillance (or so called resting) states (Boucsein et al. 2000).
2.5.6 Anion Channels
Microglial proliferation, phagocytic activity, the control of ramified morphology mainly of cell volume and microglial resting potential are all considered to be regulated by the volume-regulated Cl− channels. These channels are activated by a hypo-osmotic state. Such channels have been largely studied in microglia cultures and such cells also express the chloride intracellular channel-1 (CLIC-1). CLIC-1 play a major role in release of pro-inflammatory factors from microglia and have been considered to play an important role in progression of brain disorders.
2.5.7 Proton Channels
Functionally H+ channels are considered to be associated with the regulation of respiratory bursts in phagocytic states of microglia. These are voltage-operated proton channels with single channel conductance having high selectivity to H+. Extracellular pH is supposed to be regulating these channel expression in microglia in culture. Activated states of microglia decrease the H+ current in cell culture experiments. In respiratory bursts, activation of NADPH oxidase generates protons and superoxide anions. These ions are effluxed by H+ channels and protect the cytosol by regulating the intracellular pH.
2.6 Potent Immune Response During Brain Insult: Neuroinflammation
Neuroinflammation is an essential biological progression that stands as the foreground of various acute and chronic neuropathological conditions. Any alteration in brain’s cellular and functional integrity grounds the incidence of neuroinflammation. Neuroinflammation as a defending responder aims to refurbish the tissue homeostasis via inducing several repair processes (Goldszmid and Trinchieri 2012). However, if the regulation of this mechanism remains uncontrolled then the initial inflammatory response amplifies exceedingly and the protective mode shifts towards the collateral destruction that would further result in severe disease progression.
Neuroinflammation is a dynamic process in which both microglia and astroglia may migrate, proliferate, release potentially harmful factors (i.e. cytokines and reactive oxygen species), display different surface proteins (i.e. MHC-I/II, etc.) and blend in functions such as antigen presentation and phagocytosis in response to signals like protein aggregates, neuronal degeneration and glial products (i.e. colony stimulating factor and cytokines, etc.). Cytokine signalling following neuroinflammation is actively involved in the regulation of various brain functions like synaptic signalling modulation, neurotransmission, neuroendocrine functions and neural circuitry of behaviour and cognition (Camacho-Arroyo et al. 2009; del Rey et al. 2013; Aprile-Garcia et al. 2013; Cuartas and Jorge 2014). Therefore, it is relatively apparent to presume an altered behavioural and cognitive outcome as a consequence of a dysregulation in cytokine signalling which might result in depression, anxiety, behavioural deficits and cognitive dysfunction as observed previously (Lynch 2002; Bains and Oliet 2007; Baune et al. 2008; McAfoose and Baune 2009). Additionally in various cross-sectional and prospective population studies, it was shown that any alteration in the level of these cytokines in hippocampus lead to Alzheimer’s disease (AD), dementia and cognitive impairment (Dik et al. 2005; Magaki et al. 2007; Holmes et al. 2009; Brosseron et al. 2014).
2.7 Microglia in Immune Regulation
Following injury (Patro et al. 2005, 2010a), inflammation (Patro and Patro 2004; Patro et al. 2010b), blood–brain barrier (BBB) damage (Davies et al. 1998) or metabolic disorder (Nagayach et al. 2014a, b) associated stimuli, microglia get activated. Microglia have also been activated exogenously by various inflammatory stimuli such as lipopolysaccharide (Rivest 2003; Sharma et al. 2015), β-amyloid (Sondag et al. 2009), interferon-γ (Chao et al. 1993), thrombin (Möller et al. 2006), Poly I:C (Patro and Patro 2004), etc. for screening the stature and pathological role of activated microglia. Such activated microglia release an array of immunocompetent molecules comprising of numerous chemokines like KC, MIP-1α (Macrophage-Inflammatory Protein-1α), MIP-1β, MIP-2, MCP-1 (Monocyte chemoattractant protein-1), RANTES (regulated on activation, normal T cell expressed and secreted), IP-10 (IFN-γ-inducible protein-10), and interleukins like IL-1α/β, IL-3, IL-6, IL-10, IL-12, IL-15, IL-18, tumour necrosis factor α (TNF-α), interferon gamma inducing factor (IGIF), inflammatory proteins, TGF-β, etc. Collectively, these molecules not only control the inflammatory processes, but also regulate immune response of the brain and even contribute to neuropathogenesis in CNS inflammation. Activated microglia also promote neuroprotection by releasing anti-inflammatory molecules and growth factors like nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), basic fibroblast growth factor, etc. following immunological stimuli (Hanisch and Kettenmann 2007). In conclusion, microglia as immune regulators of the nervous system can secrete several types of molecules or express various receptors that facilitate the integration of microglial response towards the changing microenvironment (Saxena et al. 2007; Neumann et al. 2008; Patro et al. 2014).
2.7.1 Phagocytic Behaviour of Microglial Cells
Microglia that maintain homeostasis in normal cells that include phagocytic clearance of neuronal damage products or debris. During early development they are innate immune cells and clear the supernumerary synaptic processes and apoptotic neurons. In the adult CNS this phagocytic ability becomes a boon following injury and associated frequent loss of neurons and microglial recruitment at the site of injury. Such microglial presence does more than just debris clearance, which includes axonal and myelin debris in spinal cord injury or multiple sclerosis, amyloid-β deposits in AD, etc. Earlier in this review, we have explained how inefficiency of microglia not only affects clearing up the injury site but also fail reorganization of the neuronal circuits. With age, such inefficiency also enhances the prevalence of neurodegenerative disease and inadequate regeneration. However, the mechanism, action and consequence of microglial phagocytosis have not been deciphered. Thus, there is now a call for considering new therapeutic avenues involving the mechanisms of microglia-mediated tissue repair.
While phagocytosis is beneficial as it cleans up CNS and induces anti-inflammatory response but also produces toxic ROS which we have discussed above. For more details, we would refer you to Neumann and Takahashi (2007) and Sierra et al. (2013). In physiological conditions the highly motile ramified processes respond to the chemotactic ‘find me’ signals like fractalkine, ATP, UDP, etc. from apoptotic cells. Subsequently ‘Eat me’ signals, i.e. the ligands for a plethora of microglial receptors are produced by the apoptotic cells that manifest cutting and engulfing of apoptotic debris. Following this the phagocytic microglia with the help of lysosomes and other organelles finally degrade and digest the debris.
2.8 Microglial Pathophysiology Following Neuroinflammation
2.8.1 ATP Signalling
Microglia gets activated through various signalling pathways including chemokine/ chemokine receptors, nucleotides/purinergic receptors (P1, P2X and P2Y) and high-mobility group box (HMGB)/toll-like receptors. Consequently, activated microglia may secrete various soluble factors that act in inflammatory, trophic or protective manner (Suzuki et al. 2004; Di Virgilio et al. 2009). Microglia express purinergic (P2) receptors by means of elevated concentrations of extracellular ATP-induced intracellular Ca2+ elevation in a receptor-dependent manner (Fig. 2.3; Ferrari et al. 1996). Different concentrations of purine mediate ATP- and ADP-induced microglial chemokinesis and chemotaxis (Honda et al. 2001; Davalos et al. 2005). ATP signalling plays a major role not only in normal CNS function but also during the pathological states. Signals triggering microglia activation following any insult are directed by the release of purine nucleotides, comprising ADP, ATP and UTP by damaged neuronal cells (Nimmerjahn et al. 2005; Domercq et al. 2013). These signals are received by the P2Y receptors present in both microglia and astrocytes-mediating chemotactic response of microglia. During neuroinflammatory condition, the extracellular ATP concentration increase is noted that further inhibit activation and overexpression of P2X7 receptors in microglial cells.
2.8.2 Sodium Channel Signalling
Microglial voltage-gated sodium channels (Nav) are involved in a wide range of regulatory functions such as proliferation, morphological alterations, migration and phagocytosis (Eder 2005; Black et al. 2009) in response to inflammatory stimulus. Activated sodium channels stimulate a transient and rapid depolarization in microglial cells. Such depolarization of microglial cell membrane triggers the signalling cascades that further activates the microglial cell and subsequent immune activation. Furthermore, activated microglial membrane depolarization is a critical participant in the conformational change of MHC I molecule, which is essentially required for the antigen presentation functions (Bene et al. 1997). Studies on human multiple sclerosis lesions and animal models of experimental autoimmune encephalopathy (EAE), have indicated that expression of Nav 1.6 isoform of sodium channel in activated microglia gets increased (Craner et al. 2005). Consequently, the blocking of these channels was evidently used in developing the antiepileptic therapies and drugs (Black et al. 2007).
2.8.3 Potassium Channel Signalling
Inward rectifier K+ currents are generally recorded in the activated states of microglia in various pathological conditions. Insults to the nervous tissue like ischemia, peripheral nerve damage have been recorded to induce a several fold increase in the amplitudes of inward rectifier K+ channels (Boucsein et al. 2000).
The activated (delayed) receptor K+ channels in microglia are KV1.2, KV1.3 and KV1.5. The microglia in prenatal brain also express KV1.1 and KV1.2 channels. These channels are responsible for the increased delay rectifier currents in the activated state of microglia. An increased expression of delayed rectifier channels is considered as indicatives of functional responses of hyperactive microglia and during active proliferation. Such increased expression have been experimentally evidenced in microglial cells in cultures with LPS or interferon-γ (Norenberg et al. 1992), in situ following axotomy (Boucsein et al. 2000) and as a reference to microglial activation following exposure to experimental condition like in vitro exposure to LPS, interferon-γ, β-amyloid or HIV-1 regulating protein Tat, etc. (Norenberg et al. 1992; Boucsein et al. 2000). High conductance (BK) and small conductance (KCNNG/KCa3.1/SK4/IK1) type Ca2+ dependent potassium (KCa) channels are also considered to be responsible in regulation of activated state of microglia in various pathological conditions (Schlichter et al. 2010). Interestingly, studies have also reported that the stimulation of ATP-sensitive K+ channels (KATP) decreases the probability of microglial activation and are neuroprotective in several models of neurodegeneration involving neuroinflammation (Dolga and Culmsee 2012; Ortega et al. 2012).
2.8.4 Calcium Signalling
Calcium receptor activation generates two intracellular second messengers, the InsP3 and the diacylglycerol (DAG) in activated microglia which further in response activates InsP3Rs of the endoplasmic reticulum, and thus directs calcium release that regulates various cellular functions. In cell culture of rodent microglia, Ca2+ release activates Ca2+ currents (ICRAC). In activated microglia, the amplification of such currents gets decreased. ICRAC occurs after the activation of a complex of ORAI (pore forming) and STIM (Ca2+ sensor) protein (Ohana et al. 2009). Microglial cells also express a range of TRPM, TRPV and TRPC channels considered to produce intracellular Ca2+ signals regulating release of cytokines.
2.8.5 Neurotransmitter Receptors
Microglia express several neurotransmitter receptors (Färber and Kettenmann 2006a, b) such as glutamate receptors (AMPA/Kainate, NMDA receptors, metabotropic glutamate receptors, GABA, adrenergic, dopaminergic and cholintergic receptors. Interestingly, the pathological and physiological role of these receptors in microglial cells is still under investigation (Fig. 2.3). Although studies had depicted that these neurotransmitters could exert inflammatory (both pro- and anti-) effects on microglial cells (Hagino et al. 2004; Pocock and Kettenmann 2007). Like, GABA receptors can modulate the interleukin (IL-6 and IL-12) release and glutamate receptors are capable in controlling the TNF-α release. Microglial activation of metabotropic glutamate receptors induces TNF-α and Fas ligand secretion which further trigger the neuronal caspase-3 activation through Fas receptor and TNFR1 (also known as p55), leading to neuronal damage (Taylor et al. 2005). Via receiving the signals from dying neurons microglia NMDA receptor gets activated and triggers the secretion of neurotoxic factors through microglia directing towards the microglia ability of inducing and aggravating the neurological damage (Kaindl et al. 2012). In the neurodegenerative diseases like hypoxia, AD and multiple sclerosis the altered concentration and expression of glutamate receptors in microglia depict the possibility of glutamate mediated toxicity in the progression of these pathological states (Newcombe et al. 2008; Sivakumar et al. 2010). Furthermore, a lipopolysaccharide (LPS) induced activated microglia culture study shows the releases of pro-inflammatory molecules which was attenuated by the simultaneous activation of the GABA(B) receptors directing towards the role of GABA(B) receptors in the modulation of microglia immune response (Kuhn et al. 2004).
The role and relevance of ATP and calcium signalling and neurotransmitters in microglia during neuroinflammatory conditions of several pathological diseases makes them a valuable target for developing therapeutic strategies for neuroprotection. Aspects of neurotransmitter signalling in the pathophysiology of microglia have been aptly reviewed by Domercq et al. (2013).
2.9 Microglia in Neurological Diseases
Neuroinflammatory mechanism is comprised of an organized set of interaction between varied mediators like cytokines, chemokines and prostaglandins, etc. Rather than pathological conditions, the secretion of inflammatory molecules following neuroinflammation is highly influenced by the microglial activation. In response to any injury, insult or disparaged conditions, the apparent activation of microglia triggers the secretion of inflammatory molecules (Fig. 2.2) that circumstantially become superfluous at chronic glial activation (Block et al. 2007).
Microglia through various pattern–recognition receptors (like Toll-like receptors, NOD-like receptors, receptors of cell wall components or DNA/RNA of pathogens), purinergic receptors, advanced glycation endproducts receptors and scavenger receptors receive signals from injured or dying cells and vascular damage (Block et al. 2007; Brown and Neher 2010). Connections of these receptors initiate a microglial activation cascade with the expression of various proteins, comprising CD-45, COX-II, iNOS, MHC-II and various co-stimulatory molecules amongst others. These molecules facilitate the microglial expression of antigens to T cells, entered through the damaged BBB during neuroinflammation (Aloisi 2001; Carson 2005; Gertig and Hanisch 2014). Activity-dependent microglial morphological heterogenity and population segregation has previously been discussed and exemplified via the proliferative ability and/or release spectrum of the constitutive or inducible mRNAs, proteins (e.g. major histocompatibility complex class II, TNF-α, IL-6/12/1β, integrins, IGF-I, CD4/11c/34/40/86/45, FcγRII, iNOS and molecules of the neurotrophin family), superoxide anions, nitric oxide synthase and proteases, etc. redox (NOX2, NOX1, RAC1, iNOS, NOS2, etc.) and excitotoxic molecules (MGluR2, GLT-1, P2X7-R, etc.).
Furthermore, microglia also shares a bidirectional collaborative relationship with neurons that assumed to be imperative in establishing a pertinent physiological, behavioural and immunological response against any injury or disorder. Neurons via a set of unique ligand-receptor pairs (CX3CL1-CX3CR1 and CD200-CD200R), microRNA-124 (mir-124), neurotransmitters (GABA, glutamate, catecholamines), peptides and/or growth factors, CD22, CCL21, fraktalkine (that act on receptors present on microglial membrane) maintain and regulate the microglial activation (Gomes-Leal 2012; Eyo and Wu 2013).
As described above, the secretion of pro-inflammatory cytokines following microglia activation is the classic theory of neuroinflammation recognized and reviewed widely (Carson et al. 2006; Luo and Chen 2012; Boche et al. 2013). Microglia activation is generally accompanied by the proliferation of cells, mobilization towards the damaged or dying cell and the expression and secretion of pro-inflammatory cytokines, like IL-6, TNFα. IL-1β and chemokines, such as cytokine (C-C motif) ligand (CCL)2, CCL3, CCL4, CCL5, CXCL10 and/or CCL12 (Olson and Miller 2004; Semple et al. 2010). Later on, inflammatory molecules stimulate other astroglia and microglia leading to the exacerbation of glial (microglia and astroglia) activation. Furthermost alterations in cytokines expression are a result of stimulation of the transcription factor NF-κB (nuclear factor kappa enhancer of B cells) via phosphorylation-induced activation of IκB kinase (Brown and Neher 2010). Neurotransmitter signalling in the pathophysiology of microglia has been aptly reviewed by Domercq et al. (2013).
During pathological condition, cellular damage following activation of microglial cells further initiates and perpetuates the state of excitoxicity and oxidative stress within the brain. The oxidative stress and cell death caused by the microglial activation are also contributing in the generation and propagation of pro-inflammatory cytokines as documented widely (Shi et al. 2013; Sandireddy et al. 2014; Muriach et al. 2014). Furthermore, oxidative stress leads to the excessive dicarbonyl glycation which further activates the calpain expression and degrades the brain-derived neurotrophic factor (BDNF). This contributes to retard the process of neurogenesis and synaptic plasticity and stimulates NFkB-dependent inflammation and secretion of inflammatory molecules. Recurrent increment in cytokine levels increases the permeability of BBB to peripheral immune molecules and prolongs the central immune inflammatory response that generates an inordinate environment of oxidative and inflammatory stresses, accelerating CNS damage and elicits adverse structural and functional consequences. Intriguingly, reciprocal relationship between neuroinflammation, cell death and microglial activation is popularly considered as a prerequisite for the onset and pathogenesis of various psychiatric disorders like AD, PD, dementia and bipolar disorder, etc. (Hojo et al. 2004; Enciu and Popescu 2013; Najjar et al. 2013; Watkins et al. 2014).
Interestingly microglia plays a dual role during various neurological insults including neuroinflammation in CNS (Table 2.1). On the basis of secretory molecules released by the activated microglial cells microglial activation is divided into two major phases (Fig. 2.1), i.e. classical activation (M1 phase) and alternate activation (M2 phase; Colton 2009). During classical activation, microglia get triggered by the activated Toll-like receptors (TLRs) through intracellular proteins or pathogen-associated molecular patterns (PAMPs) released from injured neurons and release an array of inflammatory molecules (TNF-α, IL-6, IL-1β, IL-12), redox molecules (NOX2, NOX1, RAC1, iNOS, NOS2) and excitotoxic molecules (MGluR2, GLT-1, P2X7-R), nitric oxide synthase, superoxide anions, etc. (Ransohoff and Brown 2012; Boche et al. 2013) that further resulted in blood–brain barrier (BBB) disruption. The BBB damage promotes the infiltration of macrophages which later on exaggerate the influx of inflammatory cytokines and aggravate the existing neuroinflammatory state in CNS (Fig. 2.2; Zipser et al. 2007; Lassman et al. 2012; Obermeier et al. 2013). While in alternate activation, microglia secrete molecules like trophic growth factors, IL-4, IL-13, IL-1RA, scavenging receptors and extracellular matrix (Luo and Chen 2012; Cherry et al. 2014). Considering the imperious role of microglia in neuroinflammation, a particular attention is warranted on the microglia mediated neuro-immunological aspects of neurodegeneration and neuroregulation.
In conclusion, brain function and dysfunction, without any reservations, has a direct connection with microglial forms and functional states. They contribute to the pathogenesis and progression of various neurological disorders. Microglial activation also acts as a defence mechanism for various insults to the brain including infections. Being the immune cells of the CNS, they protect and repair the damage as also facilitate the healing process. Our understanding even today on microglial functions in normal and diseased brain is limited. Further insights on the physiology and pathophysiology of microglia using in vivo models are likely to contribute to our knowledge on the mechanisms and role of neuroinflammation for prevention or progression of brain disorders.
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The work of the authors is variously supported by the Department of Biotechnology and the Indian Council of Medical Research, Govt. of India, New Delhi.
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Patro, I., Nagayach, A., Sinha, S., Patro, N. (2016). General Physiology and Pathophysiology of Microglia During Neuroinflammation. In: Jana, N., Basu, A., Tandon, P. (eds) Inflammation: the Common Link in Brain Pathologies. Springer, Singapore. https://doi.org/10.1007/978-981-10-1711-7_2
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