Microglia: biology and pathology

Abstract

The past 20 years have seen a gain in knowledge on microglia biology and microglia functions in disease that exceeds the expectations formulated when the microglia "immune network" was introduced. More than 10,000 articles have been published during this time. Important new research avenues of clinical importance have opened up such as the role of microglia in pain and in brain tumors. New controversies have also emerged such as the question of whether microglia are active or reactive players in neurodegenerative disease conditions, or whether they may be victims themselves. Premature commercial interests may be responsible for some of the confusion that currently surrounds microglia in both the Alzheimer and Parkinson's disease research fields. A critical review of the literature shows that the concept of "(micro)glial inflammation" is still open to interpretation, despite a prevailing slant towards a negative meaning. Perhaps the most exciting foreseeable development concerns research on the role of microglia in synaptic plasticity, which is expected to yield an answer to the question whether microglia are the brain's electricians. This review provides an analysis of the latest developments in the microglia field.

Role of microglia in CNS inflammation

“…It is worth emphasizing at this point that neutrophils (granulocytes) are far more tissue destructive than macrophages [6] especially when the latter are in a M2-polarised state (CD163 positive) which has been linked to tissue repair. Interestingly, the microglia in the Parkinsonian substantia nigra show this phenotype [7]. Characteristically, granulocytes ( Fig.…”

“…For instance, we now know that microglia themselves are affected by the disease process in AD [40]. Therefore, MHC class II upregulation rather than indicating preparedness of the microglia to engage in a secondary (''recall'') immune reaction in AD, which should be accompanied by components of the classical inflammatory response (which are typically absent from AD brains), these activated microglia could be interpreted as microglia trying to protect already damaged brain tissue [7]. This could explain why anti-inflammatory drugs in AD and PD do not have the desired beneficial effects.…”

“…So in neurodegenerative diseases, widespread microglial activation may reflect widespread neuronal dysfunction in addition to the more apparent alterations of synapses. Direct neuronal attack by microglia (neuronophagia) is tightly controlled, rare and, in all likelihood, a secondary phenomenon [7]. The observation, by human neuropathologists, that microglia do not indiscriminately attack nerve cells in vivo suggests that effective neurotoxicity by activated microglia in the absence of granulocytes or T cells is unlikely or at least uncommon.…”

The L-type voltage-gated calcium channel modulates microglial pro-inflammatory activity

“…The microglial expression of the L-type VGCC described here may contribute to explaining this differential vulnerability. In pathological processes, microglia show a hybrid activation state that includes inflammatory actions and also characteristics of neuroprotection and repair (Graeber and Streit, 2010). Whether microglia adopt a phenotype that mostly exacerbates tissue injury or promotes brain repair probably depends on the diversity of signals from the lesion environment.…”

“…Microglial reaction is an early event which often precedes and triggers neuronal death in CNS pathological situations such as Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, multiple sclerosis, ischemia and brain trauma (Graeber and Streit, 2010). As a response to signals released during injury, this microglial transition from a surveillance state towards a more reactive one represents an important phenotypic change (Colton and Wilcock, 2010;Domercq et al, 2013;Kettenmann et al, 2011).…”