Emergent properties of microglia

Abstract

More than 80 years ago, Pio Del Rio-Hortega recognized that one of the "main controversial points in regard to the microglia" is "whether it belongs to the reticulo-endothelial system [i.e. monocytes and macrophages] and possesses the ordinary characteristics of this system or has a more specialized function." The notion of microglia having functions that are different from those of other macrophages has gained significant support in recent years. The brain represents a unique environment and shows species, developmental and regional specialization. Thus, any consideration of microglial activity has to be thought of in this tissue context. Contexts may be normal (health, physiology) or disease conditions showing either primary or secondary microglial involvement. Subclinical, reversible "soft pathologies" (Kreutzberg) such as pain that involves microglia also exist. Here, we examine a multilayered approach to understanding microglia that illustrates the emergent character of the microglial (population) phenotype. Accordingly, terms such as microglial "activation" and microgliosis, which are of increasing importance for our understanding of neurological disorders, need to be filled with refined meaning. It is suggested that the pathophysiological context guides nomenclatorial considerations; for example, development, trauma or pain-associated microglia is preferred over the traditional but less distinctive "microglial activation." This should also help to tease out the different functional subtypes currently hidden under the umbrella term "neuroinflammation," which is being applied so widely that it has become effectively useless in practice and even inhibits research progress because both true and pseudo-inflammation are covered by this term.

Keywords: Alzheimer's disease; emergence; inflammation; interactome; microglial activation; neurotoxicity; proteome; systems biology; transcriptome.

Figure 1

PubMed entries for “microglia” + “neuroinflammation” (2014 until early July).

Figure 2

Microglia images showing exemplary zebrafish microglia dynamically in contact with neuronal cell bodies, other microglia, neurites and the vasculature. Microglia in all images are visualized through the mpeg1:mCherry‐CAAX fluorophore transgene (represented as magenta). All images were acquired on a Zeiss LSM 710 confocal microscope with a 20× W‐Plan Apochromat (B, C and E) or a 40× W‐Plan Apochromat objective (A and D). A. Microglia (magenta) with processes contacting neurons (green) expressing the Gal4¹⁰³⁸, UAS:Synaptophysin‐GFP transgene in the Zebrafish optic tectum at 4 days post fertilization (dpf). Single slice from confocal stack with a z depth of 0.55 μm. Scale = 10 μm. B, C. Processes of adjacent microglia coming into contact. (B) and (C) are maximum projections from different regions of the same stack in the Zebrafish optic tectum at 6 dpf. (B) has a z depth of 23 μm and (C) has a z depth of 25 μm. Scale = 10 μm. D. Microglia membrane co‐localized (white) with an axon (green) in the forebrain from a hypothalamic HCRT neuron expressing HCRT: Synaptophysin‐GFP at 6 dpf. Maximum projection from a z depth of 3.47 μm. Scale = 5 μm. E. Microglial cell profiles in the brain parenchyma covering a blood vessel in the optic tectum at 8 dpf. The vascular tissue is highlighted by a standard deviation projection wherein vasculature appears white and cell masses appear grey/black (photo on the right). Maximum and standard deviation projections from a z depth of 22.6 μm. Scale = 10 μm.

Figure 3

A property, P, is an emergent property of a mereologically complex object shown in (A) if and only if P supervenes on properties and relations of the pathways of the object. P is not observed in any of the parts of the object and the object has a downward functional causal influence over its parts, constraining their relations in space‐time so that the pattern of constraints realizes (arrow) as shown in (B) and, thus, explains P [modified after 18].