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Benusa et al. Neuroimmunol Neuroinflammation 2020;7:248-63 Neuroimmunology
DOI: 10.20517/2347-8659.2020.03 and Neuroinflammation

Review Open Access

Microglial heterogeneity: distinct cell types or
differential functional adaptation?

Savannah D. Benusa , Nicholas M. George , Jeffrey L. Dupree 1,2
3
1,2
1 Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA 23298, USA.
2 Research Service, HH McGuire Veterans Affairs Medical Center, Richmond, VA 23249, USA.
3 Neuroscience Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.

Correspondence to: Dr. Jeffrey L. Dupree, Department of Anatomy and Neurobiology, Virginia Commonwealth University, 1101
East Marshall Street, Richmond, VA 23298, USA. E-mail: jeffrey.dupree@vcuhealth.org
How to cite this article: Benusa SD, George NM, Dupree JL. Microglial heterogeneity: distinct cell types or differential functional
adaptation? Neuroimmunol Neuroinflammation 2020;7:248-63. http://dx.doi.org/10.20517/2347-8659.2020.03
Received: 7 Jan 2020 First Decision: 26 Feb 2020 Revised: 15 Mar 2020 Accepted: 31 Mar 2020 Available online: 24 Jun 2020

Science Editor: Jeffrey Bajramovic Copy Editor: Jing-Wen Zhang Production Editor: Tian Zhang

Abstract
Microglia were first characterized by del Rio Hortega about 100 years ago but our understanding of these cells has
only gained traction in the last 20 years. We now recognize that microglia are involved in a plethora of activities
including circuitry refinement, neuronal and glial trophic support, cell number modulation, angiogenesis and
immune surveillance. Specific to immune surveillance, microglia detect threats which then drive their transformation
from ramified to amoeboid cells. This morphological transition is accompanied by changes in cytokine and
chemokine expression, which are far less conserved than morphology. To simplify discussion of these expression
changes, nomenclature ascribed to states of macrophage activation, known as Macrophage 1 (“M1”; classic) and
Macrophage 2 (“M2”; alternative), have been assigned to microglia. However, such a classification for microglia
is an oversimplification that fails to accurately represent the array of cellular phenotypes. Additionally, multiple
subclasses of microglia have now been described that do not belong to the “M1/M2” classification. Here, we provide
a brief review outlining the prominent subclasses of microglia that have been described recently. Additionally, we
present novel NanoString data demonstrating distinct microglial phenotypes from three commonly used central
nervous system inflammation murine models to study microglial response and conclude with an introduction of
recent RNA sequencing studies. In turn, this may not only facilitate a more appropriate naming scheme for these
enigmatic cells, but more importantly, provide a framework for generating microglial expression “fingerprints” that
may assist in the development of novel therapies by targeting disease-specific microglial subtypes.

Keywords: Microglia, neuroinflammation, single cell RNA-seq, NanoString

© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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