The International Journal of Biochemistry & Cell Biology 42 (2010) 1580–1585

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Cells in focus

Microglia: Activation in acute and chronic inflammatory states and

in response to cardiovascular dysfunction

Emilio Badoer ∗

School of Medical Sciences and Health Innovations Research Institute, RMIT University, PO Box 71, Bundoora 3083, Melbourne, Victoria, Australia

a r t i c l e i n f o

Article history:

Received 26 February 2010

Received in revised form 5 June 2010

Accepted 8 July 2010

Available online 16 July 2010

Keywords:

Myocardial infarction

Inflammation

Hypothalamus

a b s t r a c t

Microglia are the resident immune cells in the central nervous system and are constantly monitoring their

environment. After an insult, they are activated and secrete both pro­ and anti­inflammatory mediators.

Thus, they can have both detrimental and protective actions. Microglia are activated in many conditions

that involve chronic inflammation such as Alzheimer’s and Parkinson’s diseases and in neuropathic pain.

Following cerebral ischemia and stroke, microglia are activated and acutely contribute to neuronal loss

and infarct damage. Chronically, in this condition, neuroprotective actions of activated microglia include

clearance of the dead cells and secretion of neurotrophins. Of great interest is the recent observation that

following myocardial infarction, there is increased inflammation within the hypothalamus and a marked

increase in activated microglia.

© 2010 Elsevier Ltd. All rights reserved.

Cell facts

• Microglia in the ‘resting’ state appear highly branched with

a small cell soma.• ‘Resting’ microglia are motile and constantly ‘survey’ their

environment.• Microglia undergo dramatic changes in morphology and

phenotype following activation.• Upon activation microglia can up­regulate their expression

of various receptors and pro­ and anti­inflammatory media­

tors.• Microglia may contribute to the inflammatory processes

occurring in chronic conditions like Alzheimer’s and Parkin­

son’s diseases and neuropathic pain.• Microglia may also have detrimental and protective actions

in cardiovascular conditions like cerebral ischemia and fol­

lowing myocardial infarction.

1. Introduction

Microglia are the brain’s resident immune cells involved in

the surveillance of the microenvironment. Microglia are abundant

within the brain and comprise up to approximately 20% of the total

glial population. They are found in both the gray and white mat­

∗ Tel.: +61 3 9925 7081; fax: +61 3 9925 7063.

E­mail address: emilio.badoer@rmit.edu.au.

ter but are not uniformly distributed, and their density can vary

considerably between brain regions. The greatest concentrations

are found in areas that include the hippocampus, basal ganglia, and

substantia nigra. The lowest density of microglia is found in areas

that include the brainstem and cerebellum (Savchenko et al., 1997).

Microglia were first observed by Nissl staining and were subse­

quently characterized as glial cells by Ramon y Cajal. It was Ramon y

Cajal’s student, Rio­Hortega, who focussed on microglia and iden­

tified them as a separate cell population, distinct from the other

glial cells, and capable of phagocytosis. From his work he correctly

hypothesised microglia were derived from myeloid mononuclear

cells.

At rest in the adult brain, microglia have a small soma with lit­

tle perinuclear cytoplasm. Arising from the soma are several main

processes from which emanate numerous extensively branched

fine processes that are long thin and finger­like, a morphology

termed ramified (Fig. 1). The processes of microglia can contact

astrocytes, neurons and blood vessels but do not appear to contact

other microglia, and there can be 50–60 mm between individual

microglia. Recent work using time lapse photography combined

with two­photon microscopy has shown that microglia at ‘rest’ are

in fact highly motile with their fine processes undergoing cycles of

retractions and elongations that suggests sampling of the microen­

vironment (Nimmerjahn et al., 2005; Lambertsen et al., 2009; Wake

et al., 2009). Calculations of the speed of the motility of the pro­

cesses and the volume of extracellular space in the brain suggest

that the brain parenchyma can be completely sampled in a few

hours (Nimmerjahn et al., 2005). Microglia are kept in this ‘resting’

state by ‘stimulatory’ and ‘inhibitory’ signals finely balanced in the

microenvironment.

1357­2725/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.

doi:10.1016/j.biocel.2010.07.005

E. Badoer / The International Journal of Biochemistry & Cell Biology 42 (2010) 1580–1585 1581

Upon an insult to the brain tissue, such as an injury, or ischemia,

microglia become activated, markedly changing their morphology

and this is reviewed in detail by several recent reviews (Colton

and Wilcock, 2010; von Bernhardi et al., 2010). The changes

include an enlarged soma and thicker, shorter processes that have

a stubby appearance (Fig. 1). Some activated microglia become

ameboid, capable of phagocytosing debris and proliferation

(Fig. 1).

2. Cell origin and plasticity

Microglia retain the ability to divide, and to undergo DNA syn­

thesis so that they can maintain the population of microglia in

the central nervous system without reliance on peripheral, bone

marrow haematopoietic cell production. Microglia are derived

from haematopoietic progenitor cells but the exact lineage and

derivation of microglia is not known. Unlike astrocytes, oligoden­

drocytes and neurons which are derived from the neuroectoderm,

microglia are believed to derive from peripheral myeloid progen­

itor cells. Emerging evidence suggests that both extravascular and

circulating routes are used by progenitor monocytes to infiltrate

the developing central nervous system primarily in embryonic

and fetal stages of development. Perinatal microglia are pre­

dominantly in the ameboid phagocytic form which transform

into the ‘resting’ ramified morphology postnatally (Chan et al.,

2007).

During development of the central nervous system, microglia

may be responsible for the dramatic reduction in neuron numbers

via apoptotic processes and later in development microglia may

also be involved in the removal of unwanted synapses (Napoli and

Neumann, 2009). Complement proteins may be involved in this

process, however, the evidence is only circumstantial and based

on data that shows complement components are up­regulated on

activated microglia and that complement proteins can opsonize

unwanted synapses and thereby reduce neuronal connections

(Stevens et al., 2007).

3. Functions

The fundamental functions of the microglia involve protecting

the central nervous system by detecting and acting upon invading

organisms, injury or other insults. As discussed earlier, in normal

conditions, microglia are believed to constantly survey their envi­

ronment using their motile fine finger­like processes. When there

is an insult, infection, injury to the tissue, or stimulatory signals

are present in the microenvironment the microglia become acti­

vated and can undergo phenotypic and morphological changes.

These changes enable the microglia to mount a localised inflamma­

tory response by (i) up­regulation of receptors and the production

and secretion of mediators involved in inflammation, (ii) migration

to the injured region, (iii) phagocytosis, and (iv) antigen presenta­

tion.

Many receptors on resting ramified microglia may be expressed

at low levels or even not at all, but upon activation there can

be dramatic increases in their expression. Receptors found on

microglia include those activated by purines, glutamate, GABA,

catecholamines, opioids, cannabinoids, cytokines, prostaglandins,

and chemokines (see Pocock and Kettenmann, 2007 for an exten­

sive discussion). Activated microglia also dramatically increase

the expression of peripheral benzodiazepine receptors located on

mitochodria and ligands targetting these have been used as mark­

ers to image inflammation in the brain in humans (Winkeler et al.,

2010).

Neurochemicals released by activated microglia can have both

neuroprotective effects and apoptotic or neurotoxic actions. Neu­

roprotective effects may be mediated by neurotrophins (e.g. NGF,

BDNF see Fig. 1) and interleukins (e.g. IL­3 and IL­6 which may be

neuroprotective in some cases, see Fig. 1) (Inoue and Tsuda, 2009;

Napoli and Neumann, 2009). Apoptotic effects and neurotoxic

actions may be mediated by TNFa, glutamate and the generation

of reactive oxygen species such as NO, superoxide and hydrogen

peroxide (Lambertsen et al., 2009) (Fig. 1). Activated microglia can

also proliferate and this involves the actions of colony stimulat­

ing factors (CSFs), in particular monocyte CSF and granulocyte CSF,

Fig. 1. Schematic representation of resting ramified microglia which upon activation transform morphologically and can ultimately become ameboid phagocytic cells. The

reverse process may also occur when the stimulatory/inflammatory signals have subsided. Ramified microglia are constantly surveying their environment and are kept

in this state by a balance of inhibitory and excitatory signals. Microglia contain receptors or binding sites for many neurochemicals which when stimulated can activate

or propagate the activation of microglia. Receptors on microglia that are excitatory include those activated by purines (ATP and adenosine), glutamate (glu), interleukins

(IL)­1b, IL­6, IL­2, IL­4, IL­5, lysophosphatidic acid (LPA), tumor necrosis factor (TNF) a, lipopolysaccharide (LPS), toll like receptor (TLR) activation, macrophage inflammatory

protein (MIP)­1, monocyte chemoattractant protein (MCP)­1, chemokines (CC), substance P (Sub P), bradykinin (BK), prostaglandins (PGs) and the surrounding ionic milieu.

Inhibitory substances include chemokine­3­ligand 1 (CX3CL1), and possibly cannabinoids (CB) and catecholamines (CAT). GABA can inhibit LPS induced IL production by

microglia.

1582 E. Badoer / The International Journal of Biochemistry & Cell Biology 42 (2010) 1580–1585

which appear to be critical. These CSFs originate from astrocytes.

Additionally, IL­2, IL­4 and IL­5 may contribute to the proliferation

process (Inoue and Tsuda, 2009) (Fig. 1).

Various neurochemicals that regulate the migration of microglia

have been identified (Pocock and Kettenmann, 2007). These include

lysophosphatidic acid, ATP by activating P2Y12 and P2X4 recep­

tors, opioids acting on mu­opioid receptors, substance P acting on

NK1 receptors, cannabinoids acting on CB 2 receptors, and some

chemokines and trophic factors (Pocock and Kettenmann, 2007).

Fig. 1 schematically shows changes occurring during activation and

includes potential mediators.

It is critical that pro­inflammatory signals are turned off as

required, since the failure to do so may lead to the negative

impacts seen in chronic inflammation as discussed below in Sec­

tion 4. Anti­inflammatory mediators that may play an important

role in counteracting the actions of pro­inflammatory mediators

include IL­10 and fractaline (Inoue and Tsuda, 2009). These can also

emanate from microglia. Cannabinoids, GABA and catecholamines

may also reduce cytokine release from microglia (Pocock and

Kettenmann, 2007).

The receptors and neurochemicals synthesised by activated

microglia may vary between areas in the brain and according to

the state of activation of microglia (Carson et al., 2007). Thus,

it is becoming increasingly clear that the detection of a single

receptor or neurochemical as a marker of activated microglia may

not provide sufficient information on the state of activation of

microglia. In the future it is likely that molecular characteriza­

tion of microglia including high throughput microarrays will make

substantial contributions to our understanding of the changes that

occur in microglia during inflammation in the central nervous sys­

tem (Gebicke­Haertler, 2005).

Microglia are the major phagocytic cells in the central nervous

system involved in the removal of microbes, protein degrada­

tion products, apoptotic cells and other cellular debris. Phagocytic

microglia move toward an injury, the size of which determines

the number of activated microglia attracted. Exactly how this

is achieved is unclear but it is likely to involve various mark­

ers/signals that interact with membrane phospholipids on cells

and receptors on microglia. Receptors on microglia that contribute

to the phagocytosis of microbes include toll like receptors, com­

plement receptors, Fc receptors and scavenger receptors (Napoli

and Neumann, 2009). Stimulation of these receptors can also con­

tribute to the increased production of pro­inflammatory cytokines

by microglia. Phagocytosis of apoptotic cells involve receptors

on microglia that include P2Y6, which is activated by uridine

tri­phosphate released by neurons, TREM2 (triggering receptor

expressed on myeloid cells 2) and receptors that recognize phos­

phatidyl serine residues (Napoli and Neumann, 2009). Some

microglia upon activation become capable of antigen presenta­

tion to infiltrating T­cells and this involves the up­regulation of

MHC class I and II proteins and complement proteins (Yang et al.,

2010).

4. Associated pathologies

Activation of microglia has been observed in many conditions

of chronic inflammation within the central nervous system. Below

I briefly discuss Alzheimer’s and Parkinson’s diseases and neu­

ropathic pain. Before doing so, we discuss the potential roles of

microglia in cardiovascular conditions, firstly in a condition in

which there is an initial acute injury or insult to the brain (i.e.

stroke/cerebral ischemia) and secondly, a cardiovascular condition

in which there is no direct injury to the brain (i.e. following myocar­

dial infarction) but in which recent evidence highlights there is

activation of microglia.

4.1. Cardiovascular conditions: stroke/cerebral ischemia

Following a stroke or cerebral ischemia there are changes in

the morphology and phenotype of microglia, as discussed ear­

lier. Within minutes of the onset of ischemia there is activation

of microglia which peaks at approximately 72 h later, and can be

maintained for weeks after the initial insult (Napoli and Neumann,

2009). Expression of adhesion molecules on endothelial cells, leu­

cocytes and microglia contributes to the subsequent infiltration of

the damaged tissue by peripheral leucocytes, including neutrophils,

macrophages and T­cells (Napoli and Neumann, 2009). These con­

tribute to the increased production of cytokines including TNFa,

particularly from activated microglia, which are the major produc­

ers of this cytokine following ischemia (Lambertsen et al., 2009).

Acutely after a stroke or cerebral ischemia, the inflammatory

process appears detrimental to the survival of neurons. The activa­

tion of microglia has been correlated with the increase in neuronal

loss that occurs with occlusion of the middle cerebral artery in

rodents (Liu et al., 2007). Additionally, it has been shown that in

normal healthy brain microglial processes make contact with neu­

ronal synapses lasting on average approximately 5 min, and the

frequency of contacts (once per hour) decreases with reduced neu­

ronal activity. During ischemia of the brain, there is a dramatic

increase in the duration of the contact time (approximately 80 min)

that is associated with an increased loss of synapses (Wake et

al., 2009), suggesting that the enhanced contact time with neu­

rons is detrimental. The mechanisms involved in these harmful

effects are not clear. TNFa may contribute since loss of function

of this cytokine soon after the onset of ischemia reduces the infarct

damage, neuronal loss and suppresses neurogenesis. Activation of

microglia after stroke may also have neuroprotective actions and

this may also involve TNFa (Lambertsen et al., 2009). The actions

of TNFa are mediated through two subtypes of receptor. Some

studies suggest that activation of the TNF­p55 receptor elicits detri­

mental actions and activation of the TNF­p75 receptor subtype

induces protective actions. The nature of the ischemic insult and

its duration most likely induces different environmental condi­

tions in the ischemic area and this may markedly influence the

ultimate responses. For example, recent studies have shown that

activation of the TNF­p55 receptor may be neuroprotective after

ischemia induced by permanent occlusion of the middle cerebral

artery in mice (Lambertsen et al., 2009). Whatever the mechanisms,

there is some consensus in the literature suggesting that immediate

activation of microglia after an ischemic insult results in neuronal

toxicity and increased infarct damage. In the longer term, activation

of microglia appears to be neuroprotective by promoting clearance

of the dead cells and secretion of neurotrophins to promote survival

of neurons. These opposing actions occurring in inflammation may

explain why in the clinical setting, inhibition of inflammation in the

brain following stroke has not led to successful clinical outcomes

(Enlimomab Acute Stroke Trial Investigators, 2001).

4.2. Cardiovascular conditions: myocardial infarction

The studies of inflammation following the injury to the brain

tissue that occurs with stroke or ischemia have, naturally, focussed

on the roles of microglia in the acute and chronic survival of neu­

rons. Recent studies show that even in the absence of damage to

the brain, such as following myocardial infarction elicited by coro­

nary artery occlusion, there is an increase in pro­inflammatory

cytokine levels in the hypothalamus within 24 h post­myocardial

infarct. They are also elevated at the time heart failure is estab­

lished, approximately 6–8 weeks after a myocardial infarct in the

rat (Francis et al., 2004). Pro­inflammatory cytokines, such as TNFaand IL­1b, induce the production of reactive oxygen species raising

the possibility that reactive oxygen species may mediate some of

E. Badoer / The International Journal of Biochemistry & Cell Biology 42 (2010) 1580–1585 1583

the inflammatory actions of TNFa and IL­1b in the hypothalamus

in heart failure induced by myocardial infarction.

Microinjection of pro­inflammatory cytokines, e.g. TNFa, into

the hypothalamus elicits increases in renal sympathetic nerve

activity (Kang et al., 2008), most likely through the activation

of hypothalamic neurons that project to the spinal cord and

the rostral ventrolateral medulla (Shafton et al., 1998). These

sympatho­excitatory effects of the pro­inflammatory cytokines

may contribute to the abnormally elevated renal sympathetic nerve

activity seen in chronic heart failure. The mechanisms that lead to

an increase in pro­inflammatory cytokines in the hypothalamus

following myocardial infarction are not known. One hypothesis

has suggested a critical role of the pro­inflammatory cytokines

which are released into the bloodstream by the damaged heart.

These may cross the blood–brain barrier and induce local cytokine

production or induce PGE2 production in endothelial cells in the

cerebral blood vessels (Felder et al., 2003; Yu et al., 2007). PGE2 is

known to increase cytokine production. Another potential mecha­

nism includes the activation of the renin–angiotensin–aldosterone

system, which occurs following myocardial infarction. Angiotensin

II and aldosterone may act either directly or via induction of reac­

tive oxygen species to initiate the inflammatory response (Felder

et al., 2003; Guggilam et al., 2007; Lindley et al., 2004).

Recently published work suggests that activation of microglia

in the hypothalamic paraventricular nucleus (PVN) may also con­

tribute to the increase in pro­inflammatory cytokines (Rana et

al., 2010). In that study it was found that activation of microglia

was observed in the PVN at 2 weeks and at 5 weeks follow­

ing myocardial infarction. Echocardiography and haemodynamic

parameters at these times after the myocardial infarction indicated

reduced left ventricular function but congestive heart failure had

not developed, suggesting that reduced left ventricular function

was sufficient to induce activation of microglia. Furthermore, the

activation of microglia did not occur in the ventral hypothalamus

adjacent to the PVN nor in the cortex (Rana et al., 2010). This sug­

gests that there was not a wholesale breakdown of the blood–brain

barrier that could account for the activation of microglia, which

differs from other peripheral inflammatory conditions where

inflammation in the brain occurs such as inflammatory bowel

disease.

The mechanism resulting in the activation of microglia in the

PVN and not in adjacent nuclei following myocardial infarction is

not known. It is possible that changes in the neurochemical and

ionic milieu elicited by an increase in the neuronal activity in the

PVN that occurs following a myocardial infarction (Patel, 2000),

could stimulate microglia, possibly via glutamatergic or purinergic

receptor activation (Taylor et al., 2005; Hide et al., 2000). NMDA

receptors are up­regulated in the PVN in heart failure induced by

myocardial infarction in rats and this mediates an enhanced sym­

pathetic nerve response to local NMDA receptor activation (Li et

al., 2003). Interestingly, activation of microglia following restraint

stress involves activation of NMDA receptors (Nair and Bonneau,

2006). The recent finding that the activation of microglia by stim­

ulation of P2X7 purinoceptors can occur in the absence of injury or

insult to tissue (Monif et al., 2009) suggests that future investiga­

tions into the role of ATP acting on the P2X7 purinoceptors in the

activation of microglia following myocardial infarction would be

interesting. Activation of microglia in areas in which neuronal activ­

ity has been elevated by a physiological stimulus and in the absence

of local tissue damage has been previously described (Ayoub and

Salm, 2003).

Thus, it is speculated that activated microglia could con­

tribute to the increased local production of pro­inflammatory

cytokines observed in the hypothalamic paraventricular nucleus

following myocardial infarction and resulting reduced left ven­

tricular function. The activation of microglia induces secretion of

Fig. 2. A schematic representation showing that activated microglia may contribute

to the increased local production of pro­inflammatory cytokines observed in the

hypothalamic paraventricular nucleus (PVN) following myocardial infarction. The

mechanisms responsible for the activation of microglia that occurs after a myocar­

dial infarction are unknown but may involve elevated plasma levels of angiotensin II,

aldosterone, and cytokines, or changes in the local milieu within the paraventricular

nucleus such as increased glutamate (Glu) and ATP. Activation of microglia induces

secretion of pro­inflammatory cytokines, such as TNFa and IL­1b, can activate

hypothalamic paraventricular neurons that project to the spinal cord where sym­

pathetic preganglionic (SPN) motor neurons are located. Increased activity of these

neurons increases sympathetic nerve activity. In heart failure there is increased

sympathetic nerve activity to the kidneys (RSNA). Thus, it is speculated that chronic

activation of microglia may contribute to the elevated sympathetic nerve activity

seen in chronic heart failure. Abbreviations: III, third ventricle; PGN, post­ganglionic

neuron.

pro­inflammatory cytokines that may activate hypothalamic par­

aventricular neurons that regulate sympathetic nerve activity. This

may contribute to the elevated sympathetic nerve activity seen in

chronic heart failure. The mechanisms responsible for the activa­

tion of microglia are unknown but the presence of glutamate and

ATP may be involved (Fig. 2).

4.3. Alzheimer’s disease

Alzheimer’s disease is a debilitating neurodegenerative disease

that causes cognitive impairment in patients. The common char­

acteristics of Alzheimer’s disease is the formation of extracellular

amyloid b plaques and intracellular neurofibrillary tangles. Amy­

loid b is cleaved from membrane bound precursors via b and gsecretases to produce soluble and insoluble isoforms. Amyloid bcan activate microglia resulting in increased secretion of inflamma­

tory cytokines, reactive oxygen species and phagocytosis. Microglia

migrate to amyloid plaques (Bolmont et al., 2008), and since the

expression of CD14 receptors on microglia increases in inflamma­

tion (this receptor has been implicated in amyloid b removal) this

could lead to an increased phagocytosis of amyloid plaques. This

may involve toll like receptors (Richard et al., 2008). Enhanced

expression of complement proteins in activated microglia have also

been implicated in the removal of amyloid b. However, increased

expression of pro­inflammatory cytokines and other proteins such

as prostaglandin and cyclo­oxygenase may actually enhance amy­

loid b deposition. Thus, activated microglia in Alzheimer’s disease

may have both positive and negative effects. The current view is

that the useful actions of activated microglia occur acutely follow­

ing activation of microglia but with continued chronic activation of

microglia, as occurs in Alzheimer’s disease, the detrimental actions

of activated microglia predominate in this disease (Schlachetzki

and Hull, 2009).

1584 E. Badoer / The International Journal of Biochemistry & Cell Biology 42 (2010) 1580–1585

4.4. Parkinson’s disease

Parkinson’s disease affects mainly older individuals and as the

population ages, it is expected that the incidence of this disease

will increase. It is characterized by loss of dopaminergic neurons

in the substantia nigra and affects motor control that can result

in tremors, rigidity and loss of balance (Long­Smith et al., 2009).

Accompanying the loss of dopaminergic neurons, there is increased

activation of microglia, increased production of pro­inflammatory

cytokines and inflammatory mediators (Long­Smith et al., 2009).

Inflammatory processes are believed to play an important role

in the aetiology and progression of Parkinson’s disease since

epidemiological studies show that regular use of non­steroidal

anti­inflammatory agents is associated with reduced incidence of

Parkinson’s disease. The increase in activated microglia is observed

in human post­mortem brain tissue and in the brains of animals

in which Parkinson’s disease symptoms have been induced (e.g.

with MPTP, LPS) (Liu, 2006). Activated microglia are found mainly

in the substantia nigra but are not restricted to that brain region.

Animal studies have been important in correlating the activation

of microglia and damage to dopaminergic neurons. In common

models of Parkinson’s disease, microglia are activated rapidly and

maximum numbers of activated microglia are observed within days

corresponding to the increasing damage of dopaminergic neurons

(Liu, 2006). Various pro­inflammatory mediators are increased in

the brains of patients who suffered from Parkinson’s disease, and

in animal models. These mediators include TNFa and IL­1b, whose

receptors are up­regulated in dopaminergic neurons suggesting

these contribute to the damage and subsequent loss of those neu­

rons.

4.5. Neuropathic pain

Neuropathic pain is a chronic pain occurring following sensory

nerve injury and is often accompanied by tactile allodynia. Neu­

ropathic pain is not relieved satisfactorily by currently available

analgesics and non­steroidal anti­inflammatory agents. Neuro­

pathic pain is characterized by hyper­excitability of dorsal horn

neurons. Activation of microglia occurs within hours of nerve injury

and is increased 2–4­fold within days. There are many signals that

have been reported to be involved including purines (Burnstock,

1997). In allodynia the P2X4 purinoceptor appears to be partic­

ularly important (Burnstock, 1997; Inoue and Tsuda, 2009). The

expression of this receptor is increased markedly in microglia in

dorsal root ganglia following peripheral nerve injury. Activation of

this receptor is necessary and sufficient for neuropathic pain and

tactile allodynia (Inoue and Tsuda, 2009). Other purinoceptor sub­

types that are up­regulated and may contribute to the symptoms of

neuropathic pain include P2X7 and P2Y12. Chemokines including

CCL2, CX3CR1, and receptors including TLRs and cannabinoid B2

are also increased on microglia following nerve injury (Inoue and

Tsuda, 2009).

5. Conclusion

Microglia are the resident immune cells in the central nervous

system and are constantly monitoring their environment. At the

first signs of an insult or injury to the tissue, they become activated

and secrete both pro­ and anti­inflammatory mediators. Thus they

can have both detrimental and protective actions. Microglia are

activated in many conditions that involve chronic inflammation

such as Alzheimer’s and Parkinson’s diseases and in neuropathic

pain. Following cerebral ischemia and stroke, microglia are acti­

vated and acutely contribute to neuronal toxicity and infarct

damage. Chronically, protective actions of activated microglia

include clearance of the dead cells and secretion of neurotrophins.

Of great interest is the recent observation that following myocardial

infarction, there is increased inflammation within the hypothala­

mus and a marked increase in activated microglia. It remains to

be established as to whether this contributes to the dysregulation

of sympathetic nerve activity observed in chronic heart failure fol­

lowing myocardial infarction. The imaging of microglia in vivo will

provide greater insight into the processes involved in their activa­

tion in neuropathological and neuroinflammatory conditions, and

the expression of different receptors and an understanding of the

signalling cascade mediating the activation of microglia are likely to

contribute to the development of novel therapies for neuropatho­

logical conditions such as Alzheimer’s disease and cardiovascular

diseases like stroke and heart failure.

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