The changing phenotype of microglia from homeostasis to disease

Luo, Xiao-Guang; Chen, Sheng-Di

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] [20] [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] [32] [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.