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.

Keywords: Depression; Homeostasis; Inflammation; Microglia; Parainflammation; Stress.

Fig. 1

Phenotypic distinctions between homeostatic and “activated” microglia. Under typical conditions (A), microglia display a ramified morphology and a unique pattern of gene expression, making them identifiable through a number of different techniques. However, a variety of immunogenic stimuli can elicit dramatic morphological and functional changes in microglia. Immunologically activated microglia (B) possess an amoeboid morphology; marked by increased soma size and less ramified processes. Markers for microglia activation vary widely depending on the type and severity of insult, but surface proteins associated with classical immune functions (e.g., antigen presentation, phagocytosis) tend to be increased, while those associated with homeostasis may be reduced. Functions of activated microglia are also highly variable, with the same cells potentially driving tissue damage and repair processes simultaneously. Morphological features may not correspond to assumed functional roles. Nonetheless, classical immune functions of activated microglia include phagocytosing cellular debris, large increases in cytokine signaling, recruitment of peripheral immune cells to the parenchyma, and destroying infected or dying cells

Fig. 2

Contrast between neuroinflammation and parainflammation. Neuroinflammation (left) describes immune-driven pathology which occurs in the course of disease, injury, or infection in the brain. This tissue state can be identified by four common molecular and cellular hallmarks illustrated on the left. These are: (1) high levels of pro-inflammatory cytokines, (2a) microglia and (2b) peripheral macrophage activation, (3) infiltration of peripheral leukocytes (e.g., bone-derived monocytes, T cells) to the parenchyma, and tissue damage such as (4a) BBB breakdown and (4b) neuron death. Neuro-immune systems can also be engaged by homeostatic challenges (i.e., psychological stress), leading to an intermediate tissue state termed parainflammation (right). While a formal definition of parainflammation is yet to be widely accepted in neuroscience, neuro-immune interactions previously reported in parainflammatory contexts are shown on the right. These include: (1) microglial recruitment of bone-derived monocytes to the perivascular space, (2) changes in cytokine signaling between neurons and microglia, (3) microglia-mediated neuronal remodeling, and (4) diffusion of small signaling peptides across the BBB