What is microglia neurotoxicity (Not)?

Abstract

Microglia most likely appeared early in evolution as they are not only present in vertebrates, but are also found in nervous systems of various nonvertebrate organisms. Mammalian microglia are derived from a specific embryonic, self-renewable myeloid cell population that is throughout lifetime not replaced by peripheral myeloid cells. These phylogenic and ontogenic features suggest that microglia serve vital functions. Yet, microglia often are described as neurotoxic cells, that actively kill (healthy) neurons. Since it is from an evolutionary point of view difficult to understand why an important and vulnerable organ like the brain should host numerous potential killers, we here review the concept of microglia neurotoxicity. On one hand it is discussed that most of our understanding about how microglia kill neurons is based on in vitro experiments or correlative staining studies that suffer from the difficulty to discriminate microglia and peripheral myeloid cells in the diseased brain. On the other hand it is described that a more functional approach by mutating, inactivating or deleting microglia is seldom associated with a beneficial outcome in an acute injury situation, suggesting that microglia are normally important protective elements in the brain. This might change in chronic disease or the aged brain, where; however, it remains to be established whether microglia simply lose their protective capacities or whether microglia become truly neurotoxic cells.

Resident microglia, rather than blood‐derived macrophages, contribute to the earlier and more pronounced inflammatory reaction in the immature compared with the adult hippocampus after hypoxia‐ischemia

“…Based on this study and previous reports, we found that the observed expression of galectin‐3, rather than the differences in the time‐course of the two M1 and M2 phenotype macrophage markers after HI between the immature and the mature hippocampus, correlated with the age‐dependent effects of HI (Fernández‐López et al, 2014). However, a single M1 or M2 phenotype marker does not classify individual microglia as pro‐ or anti‐inflammatory, rather, the combined expression of multiple markers produce a continuous spectrum of functional heterogeneity (Biber et al, 2014), and more comprehensive approaches are needed to more accurately phenotype individual microglia.…”

Knockout of fractalkine receptor Cx3cr1 does not alter disease or microglial activation in prion-infected mice

“…Whilst Cx3cr1 knockout experiments in Parkinson's disease, ALS and Alzheimer's disease models have indicated a role for CX3C signalling (Cardona et al, 2006;Lee et al, 2010;Cho et al, 2011), our experiments suggest that CX3CR1 is not essential to the microglial response in prion disease. As others have proposed, some redundancy may exist in the signalling mechanisms that regulate microglia (Biber et al, 2014), thus other molecules such as CD200/CD200R and/ or TREM2 may play an augmented role upon deletion of Cx3cr1 in prion disease models.…”

“…During activation, microglia undergo morphological changes, proliferate, migrate and produce cytokines and chemokines in reaction to central nervous system (CNS) infection and injury. Whilst this activation has homeostatic functions, it can also be neurotoxic and contribute to disease progression (Biber et al, 2014;Ransohoff et al, 2015).…”

“…Within the CNS, the receptor for fractalkine (CX3CR1) is expressed exclusively by microglia (Hughes et al, 2002;Jung et al, 2000). Cell surface expression of and/or release of CX3CL1 from neurons is believed to preserve the quiescent state of microglia (Biber et al, 2007;Wolf et al, 2013) and thus prevent potentially neurotoxic effects of microglial activation (Biber et al, 2014;Limatola & Ransohoff, 2014). Therefore, signalling via the CX3C axis may be critical to microglial response in neurological disease.…”

“…Although studies of Cx3cr1 knockout (Cx3cr1-KO) mice in several models of neuroinflammatory disease have yielded interesting results, conclusions on the role of CX3C signalling on microglia are still diverse and vary with experimental system used (Wolf et al, 2013;Biber et al, 2014). For example, in two different Alzheimer's disease mouse models, deletion of Cx3cr1 resulted in a reduction in b-amyloid deposition (Lee et al, 2010;Prinz et al, 2011).…”