Neuroinflammation has long been considered a mediator of secondary damage following a small injury to the CNS. As the primary immune cells in the brain, microglia are expected to take active roles in the damage process. The presence of activated microglia within injured brain regions and in post-mortem tissue from patients having various neurodegenerative disorders has led to the assumption that all reactive microglia contribute to an adverse and degenerative process. Further studies describe destructive roles for microglia by demonstrating the release of a range of neurotoxins from microglia that includes pro-inflammatory cytokines [
19‐
21], nitric oxide [
22,
23] and reactive oxygen species [
24,
25]; the inhibition of microglial activation in various experiments results in the attenuation of neurotoxic events and improves neuronal survival. In various neurodegenerative disorders, the over-activation of microglia is considered to be a key causative factor in the process or, at a minimum, to promote the neuropathology. For example, in Alzheimer’s disease, microglia activated by amyloid-β(Aβ) protein, the hallmark of the disease, release neurotoxins and potentiate neuronal damage, and this microglial over-activation is an early event that precedes neuropil destruction [
26]. The activated microglia cluster around or penetrate the neuritic plaques [
27], supporting a critical role of microglial activation in the pathogenesis and progression of the disease. In Parkinson’s disease (PD), an increased number of activated microglia are present in the vicinity of degenerating neurons [
28] in the substantia nigra [
29], which is particularly deleterious to dopaminergic neurons due to their glutathione deficiency [
30]. A single injection of lipopolysaccharide (LPS) to activate microglia in the substantia nigra region led to a progressive, preferential and irreversible loss of dopaminergic neurons [
31‐
33], even though LPS itself did no direct harm to the neurons, indicating that the over-activation of microglia is capable of inducing neuronal death in the absence of other pathological stimulation. All of the evidence described above supports the hypotheses of the neurotoxic features of microglia.
However, as the sentinel and essential cells of the CNS, it is unlikely that microglia would function to damage neurons in all scenarios. Once stimulated the microglia migrate rapidly to the injury site along the chemokine gradients in vitro [
34] and also in response to chemoattractants including ATP and NO released directly or indirectly by the injury [
35] to exert effect on the survival of neurons. In fact, some specifically designed experiments have begun to uncover the neuroprotective roles of microglia, and more studies are emerging to show beneficial functions of microglia. Firstly, studies have demonstrated instructive roles for microglia in the developing brain for neuronal differentiation [
36,
37] and in the regulation of neuronal apoptosis [
38] through the production of neurotrophins [
39]. Secondly, in the adult brain, resting microglia, which are characterized by many fine perpendicular processes extending from a few long prolongations, have been regarded as sensor cells for the detection of abnormalities or changes in the brain [
40] and help to maintain environmental homeostasis. Lastly but most importantly, activated microglia have also been shown to perform neurotrophic functions following neuronal injury. One compelling study supporting this finding involves the axotomy of peripheral nerves (facial or optic), where a rapid microglial response is exhibited with the efficient clearance of myelin debris that contained inhibitory molecules of axon growth, finally leading to successful axonal regeneration [
41]; the inhibition of this microglial response to facial nerve axotomy impairs neuronal survival [
42]. In addition, in neonatal mice administered MPTP, highly activated microglia show neurotrophic potential towards dopamine neurons [
43] and after traumatic injury, clear glutamate without evoking inflammatory mediators [
44]. The benefits of microglial activation are further demonstrated by the exacerbation of neuropathology in inducible mouse models that are deficient in microglia [
45,
46], the finding of protective microglia in cases of cerebral ischemia [
47] and multiple sclerosis [
48] and the fact that transplantation of microglia can help to enhance neurite growth and functional recovery after CNS injury [
49,
50]. The bunch of factors that can activate microglia and the differential behavior of microglia in various conditions have been listed in Table
1 &
2. The above studies clearly demonstrate that microglia can be neurotrophic in the proper situations; there might be a third possibility that microglia are activated by simply reacting to pathogenic stimulation and takes very limited roles in the neurological disorders, in such case the activation of microglia is solely a result of pathogenic stimulation and work as a by-stander that either involved passively during the whole process or even go to apoptosis by some other signals. Thus These activated microglia might have different phenotypes. However, the details of what conditions induce microglia to take beneficial phenotypes remain unknown. Many factors are likely involved in determining the eventual outcome of the manifestation of microglia, including their interaction with neurons or astrocytes in the same environment, age-related dysfunction of microglia, activation timing, and the activation state of the microglia, which we will be discussing below.
Table 1
Factors that can activate microglia
Pathological conditions
|
hypoxia | Morigiwa et al., 2000 [ 51] |
tumor | |
Ischemic insult | |
Nerve injury | |
Proteins
|
α-synuclein | Lee et al., 2010; Su et al., 2008; Zhang et al., 2005 [ 55‐ 57] |
amyloid-beta | |
fibrinogen | |
Thrombin | |
Tissue plasminogen activator | |
Matrix protein (vitronectin, fibronectin, MMP-3) | Milner et al., 2007; del Zoppo et al., 2007; Kim et al., 2005 [ 62‐ 64] |
Chemicals
|
Adenosine Triphosphate | |
Toxins (MPTP, Rotenone, Paraquat) | Yasuda et al., 2008; Gao et al., 2002; Wu et al., 2005 [ 66‐ 68] |
Alchohol | McClain et al., 2011 [ 69] |
Dopamine quinone | |
Berberine | |
lipopolysacchride | Jung et al., 2010; Meng et al., 2008; Xu et al., 2009 [ 72‐ 74] |
Cytokines
|
TNF-α | Iribarren et al., 2005 [ 75] |
IL-6 | |
IL-12 | Tamakawa et al., 2004 [ 77] |
IL-3 | Natarajan et al., 2004 [ 78] |
IFN-Υ | Rozenfeld et al., 2005; Hall et al., 1999 [ 79, 80] |
Others
|
gangliosides | Kim et al., 2009; Min et al., 2004 [ 81, 82] |
Kalic acid | Zheng et al., 2010; Zhu et al., 2010 [ 83, 84] |
Table 2
Behavior of microglia in different conditions
In steady state
|
Healthy resting state | Surveillance, homeostasis [ 85] Fixed cell and motile processes, minimal expression of cell surface markers and release of cytokines and chemokines, not involved in Phagocytosis |
In disease state
|
Neuroprotective
|
Axotomy of the optic nerve | Efficient clearance of myelin debris [ 41] |
Traumatic injury | Clear glutamate without evoking inflammatory mediators [ 44] |
Ischemia | Synthesis of tumor necrosis factor, engulfment of harmful invading neutrophil granulocytes [ 86] |
Alzheimer’s Disease | Internalize and degrade amyloid beta [ 87] |
Multiple sclerosis | Secrete soluble mediators that trigger neural repair and usually contribute to the creation of an environment conductive for regeneration [ 48] |
Neurotoxic
|
Parkinson’s disease | Releasing various kinds of noxious cytokines, reactive oxygen species [ 88] |
Multiple sclerosis | Express iNOS [ 89] and generate toxic ROS which might injure neurons |
Alzheimer’s disease | Produce of chemokines, neurotoxic cytokines and reactive oxygen an dnitrogen species that are deletrious to the CNS [ 90] |