Microglial heterogeneity: distinct cell types or differential functional adaptation?

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.

Improved cognition impairment by activating cannabinoid receptor type 2: Modulating CREB/BDNF expression and impeding TLR-4/NFκBp65/M1 microglia signaling pathway in D-galactose-injected ovariectomized rats

“…According to Prinz et al study [ 9 ], advances in imaging and genetics of single-cell technologies provided new insights into the much more complex and fascinating microglia biology. However, the advantage of the "M1/M2" classification is that it gives a simplified nomenclature to distinguish between microglia in functionally distinct states [ 10 ].…”

The Central Nervous System Source Modulates Microglia Function and Morphology In Vitro

“…However, the flow cytometry data support the observation that the phagocytosis capacity of microglia in vitro is distinct according to their CNS spatial origin, as the spinal-cord-derived microglia are less phagocytic (Figure 2C). It is important to highlight that environmental cues modulate microglial transformation from a surveying to phagocytic function differently [36], and the effect observed with microspheres should also be tested with other engulfed substrates present in the CNS tissue context, such as synaptosomes, myelin debris, or apoptotic cells [37][38][39][40]. Here, we observed that the impact of unique signals from the cortex or spinal cord microenvironment on microglial cell machinery is most likely conserved in vitro, resulting in different phagocytic capacities.…”

Glial Contributions to Lafora Disease: A Systematic Review

“…Our analysis of data from transcriptomic [ 21 ] and PCR analyses [ 18 , 22 , 39 , 62 , 63 , 66 ] performed in mouse models of LD revealed the upregulation of several genes characteristically expressed in proinflammatory microglia [ 33 , 73 , 74 ], such as lipid-metabolism- and phagosome-related genes (Cst7, Lyz2, Clec7a, Axl, and Itgax), cathepsins (Ctss and Ctsz), major histocompatibility complex (MHC-II)-related genes (H2-D1 and H2-K1), proinflammatory genes (Tlr2, Il1b, and TNFa), and Trem2, a receptor required for DAM activation [ 75 ]. One of these studies [ 39 ], performed in a 12-month-old Epm2b KO mouse model, also showed the upregulation of several anti-inflammatory genes such as IL-10, IL-10ra, TGF-β, S100A-10, IL-13, IL-4, ARG-1, and CD206, which are characteristic of glia polarized towards a protective phenotype.…”