The semantics of microglia activation: neuroinflammation, homeostasis, and stress

Abstract

Microglia are emerging as critical regulators of neuronal function and behavior in nearly every area of neuroscience. Initial reports focused on classical immune functions of microglia in pathological contexts, however, immunological concepts from these studies have been applied to describe neuro-immune interactions in the absence of disease, injury, or infection. Indeed, terms such as ‘microglia activation’ or ‘neuroinflammation’ are used ubiquitously to describe changes in neuro-immune function in disparate contexts; particularly in stress research, where these terms prompt undue comparisons to pathological conditions. This creates a barrier for investigators new to neuro-immunology and ultimately hinders our understanding of stress effects on microglia. As more studies seek to understand the role of microglia in neurobiology and behavior, it is increasingly important to develop standard methods to study and define microglial phenotype and function. In this review, we summarize primary research on the role of microglia in pathological and physiological contexts. Further, we propose a framework to better describe changes in microglia1 phenotype and function in chronic stress. This approach will enable more precise characterization of microglia in different contexts, which should facilitate development of microglia-directed therapeutics in psychiatric and neurological disease.

Microglial P2Y12 mediates chronic stress-induced synapse loss in the prefrontal cortex and associated behavioral consequences in male mice

“…Intriguingly, these same studies found no differential expression of inflammation-associated molecules, suggesting that MDD is not marked by microglial ‘activation’ or neuroinflammation, but rather a more nuanced shift in microglial phenotype. This parainflammatory phenotype is observed in several models of chronic stress [36]. Given our data, it is interesting to speculate that microglial P2Y12 may play an important role in regulating synapse loss in MDD.…”

Increased Monocyte Production of IL-6 after Toll-like Receptor Activation in Children with Autism Spectrum Disorder (ASD) Is Associated with Repetitive and Restricted Behaviors

“…In addition to being first-line defenders in the CNS, these myeloid-derived cells are critical for homeostasis in the brain. They have inflammatory capabilities when activated, and produce IL-6 under inflammatory conditions [ 54 ]. Genes associated with microglial activation are upregulated in the postmortem ASD brain [ 55 , 56 , 57 ].…”

The microbiota promotes social behavior by modulating microglial remodeling of forebrain neurons

“…Our ccl34b.1 + population (“amoeboid” cluster 1) likely corresponds to optic tectum-enriched neurogenic associated microglia (NAMs) and our ccl34b.1 - population (“ramified” cluster 4) likely corresponds to hindbrain-enriched synaptic-region associated microglia (SAMs) [62]. Separating microbial modulation of gene expression in distinct microglial functional subtypes enables us to identify homeostatic, neuroinflammatory, and parainflammatory effects of the microbiota [86]. In amoeboid cluster 1 NAMs the microbiota restrains expression of migration and chemotaxis genes while promoting expression of genes linked to lysosomal function, nucleotide metabolism, and mitochondrial function.…”