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. 2013 May 14:7:65.
doi: 10.3389/fncel.2013.00065. eCollection 2013.

Functional diversity of microglia - how heterogeneous are they to begin with?

Uwe-Karsten Hanisch  1
Affiliations

Functional diversity of microglia - how heterogeneous are they to begin with?

Uwe-Karsten Hanisch. Front Cell Neurosci. .

Abstract

Microglia serve in the surveillance and maintenance, protection and restoration of the central nervous system (CNS) homeostasis. By their parenchymal location they differ from other CNS-associated myeloid cells, and by origin as well as functional characteristics they are also-at least in part-distinct from extraneural tissue macrophages. Nevertheless, microglia themselves may not comprise a uniform cell type. CNS regions vary by cellular and chemical composition, including white matter (myelin) content, blood-brain barrier properties or prevailing neurotransmitters. Such a micromilieu could instruct as well as require local adaptions of microglial features. Yet even cells within circumscribed populations may reveal some specialization by subtypes, regarding house-keeping duties and functional capacities upon challenges. While diversity of reactive phenotypes has been established still little is known as to whether all activated cells would respond with the same program of induced genes and functions or whether responder subsets have individual contributions. Preferential synthesis of a key cytokine could asign a master control to certain cells among a pool of activated microglia. Critical functions could be sequestered to discrete microglial subtypes in order to avoid interference, such as clearance of endogenous material and presentation of antigens. Indeed, several and especially a number of recent studies provide evidence for the constitutive and reactive heterogeneity of microglia by and within CNS regions. While such a principle of "division of labor" would influence the basic notion of "the" microglia, it could come with the practival value of addressing separate microglia types in experimental and therapeutic manipulations.

Keywords: TLR; cytokines; diversity; experience; immunity; innate; microglia; subtypes.

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Figures

FIGURE 1
FIGURE 1
Schematic overview of the conceptual framework and some supporting findings pointing to a heterogeneity of microglial properties. (A) In the normal CNS tissues, microglia comprise a population of myeloid cells with parenchymal distribution. The ramified morphology and a low expression of immune function-related molecules were formerly taken as signs of a “resting” status. This view got corrected upon demonstration of active tissue surveillance and periodic inspection of synapses with their motile processes. Nevertheless, by morphology and immunophenotype, microglia may still largely appear as a homogeneous cell type, although regional differences exist regarding density, morphology, capacity for proliferation and expression of certain proteins (or antigenic structures). On the other hand, subtle or yet unidentified variations in house-keeping duties (such as the nursing of synapses) and latent capacities may exist that define subtypes among and within anatomical subdivisions. (B) One of the duties unequally performed by microglia under physiological conditions relates to the macropinocytotic uptake of myelin-laden exosomes as they are emitted by oligodendrocytes in a principle of “outsourced” myelin turnover. Upon a challenge, such as by IFNγ, this subset of microglia reveals a lack of MHC II expression, in opposition to a largely complementary portion of cells that readily upregulate the surface structure for (potential) professional antigen presentation – but, in turn, do not engage with the exosomal clearance. As a purpose of this division of labor, immunologically silent disposal of endogenous material can take place in a sequestered compartment. (C) Challenges by bacterial agents, like LPS, or probably also appearance of endogenous factors with a connotation of damage and a similar TLR4-agonistic activity, can induce the synthesis of TNFα, which can then affect the vitality and functionality of resident as well as infiltrating (immune) cells. Since the production appears to be a privilege of some microglia only (even within local cell communities), they could claim the role of an instructor role or maître de plaisir during a response. TNFα-producing cells further subdivide by the ability or inability to also release CCL3. Yet the organization of such responder subtypes could be based on entirely different principles. Cellular subsets could be predetermined as to their functional capacities, acquire such distinction by environmental cues or regulate activities in a stochastic process. The scheme was adapted from previous own work (Hanisch and Kettenmann, 2007; Scheffel et al., 2012).
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