Microglia rules: insights into micoglial–neuronal signaling

Activation of microglia, which are the resident, intrinsic arm of the CNS innate immune defense, has long been considered as bystander phenomenon of neuropathology, simply acting as scavenger cells. Considering the enormous capacity of biosynthesis after activation, microglia was then widely confined to detrimental aspects of the immune response culpable of for amplification of CNS damage (promoting oxidative burst, expression of proteases, BBB damage).¹ Subsequently, this perspective was opposed by beneficial microglial features such as neuroprotection mediated by a plethora of neurotrophins and glutamate channels (trapping glutamate excess at the synapse, thereby reducing excitatoric injury, ‘glutaminergic escape’).^{2, 3, 4}

In addition, activated microglia/macrophages are essential for effective tissue debris removal constituting a prerequisite for efficient remyelinization.⁵ Finally, activated microglia/macrophages were reported to alter the nonpermissive nature of the CNS promoting axonal growth,⁶ thereby stimulating axonal regeneration.^{7, 8} This functional dichotomy has been related to local and temporal environmental changes during CNS lesion maturation. This suggested a beneficial or detrimental microglia mode specific for a distinct stimulus.^{9, 10} Thus, ‘activated microglia’ is not ‘activated microglia’ and the elicited functional effect is dependent on its corresponding environment, which is persistently changing during evolution of an acute lesion. This concept has been recently confirmed demonstrating CNS axon regeneration to be sensitive to the time of microglia activation, identifying day 3 after acute injury as most beneficial.⁸ However, until now, microglia activation modes can still only be categorized as different activation levels (alert, activated, super-activated). This is opposed by little evidence for a specific microglia activation mode categorized as beneficial or detrimental.

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