The changing phenotype of microglia from homeostasis to disease

Luo, Xiao-Guang; Chen, Sheng-Di

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 bystander 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.