Microglia: Neuroimmune Wardens and Synaptic Pruners of the CNS

The nervous system, for all its complexity and astounding functional products, is compromised in its mechanisms for regeneration and repair. Unlike the tissue making up our skin, lungs, intestines, and liver, nervous tissue is greatly limited in its generation of new cells. Given its deficient regenerative properties and restrained mending mechanisms, the brain relies instead on its plasticity, employing intact neuron and circuit reorganization after suffering injury rather than cell renewal (1). Nonetheless, it is not entirely devoid of manners of defense and response. Among the cell populations that compose the central nervous system, there exists a glial subtype known as microglia which account for 10-15% of all cells in the brain (1). These myeloid cells immigrate from the periphery and spread out throughout the central nervous system early in development, embedding themselves in the brain parenchyma (3). Microglia embody the CNS’s primary neuroimmune response against brain insult or injury and, ideally, seek to maintain CNS homeostasis. In a healthy brain, microglia in their default “ramified” state act as active tissue scanners, constantly monitoring the cellular environment for indications of damage or dysfunction (4). If signs of these are detected, the dynamic wardens undergo a highly regulated process of enzymatic and morphological transformation which results in motile, immunoregulatory, and phagocytotic activity. 

Microglia’s first notable scientific feature occurred in Pio del Rio-Hortega’s visionary and eponymous chapter (8) which was mainly based on his experiments using silver carbonate impregnation to label the cells. Del Rio-Hortega’s observations and postulates about the morphological versatility of these cells, their origin, and function influenced much of the subsequent research performed on microglia and many of his statements are still viewed as valid today. Further research on microglia has elucidated the complexity and diversity of their mechanisms and roles in the brain. Primarily, they act as initiators and mediators of neuroimmune action.

Microglial activation is “triggered when microglia perceives the sudden appearance, abnormal concentration, or unusual molecular format of certain factors” (3). The process entails a chain of changes in gene expression, cell shape, functional behavior and, consequently, targeted movement toward the damaged area through a chemotactic gradient. This directed response possibly depends “on purinoreceptor stimulation and may involve assistance from astrocytes” (4). At the site of injury or alert, effector microglia can act as macrophages to clear out cellular debris (i.e. dead cells or compartments) and invasive microbes. Moreover, they have the ability to secrete neurotrophic and immunoregulatory factors, proinflammatory compounds, and present antigens which may aid adaptive immunity against future viral or bacterial infections in the brain. Microglial cells also have neurotransmitter receptors as well as cytokine/chemokine receptors, allowing the reception of signals corresponding to other types of glial cells, neurons, and immune cells (3). This capacity for bi-directional communication between microglia and nerve cells or immune cells is key to their surveillance and activated function.

Furthermore, microglia form part of what has been described as the CNS’s “immune privilege”. The idea of the CNS having immune privilege arose after a series of experiments which highlighted the brain’s higher tolerance to tumor transplants in comparison with the periphery and its failure “to mount an efficient immune response against an allogeneic graft” (7). Currently, the concept refers to the CNS’s unique repertoire of neuroimmune mechanisms to maintain brain homeostasis and to limit the damaging consequences of an inflammatory response in the brain following injury (2, 7). It has been established that “immune privilege, involving both innate and adaptive immune responses, is limited to the CNS parenchyma proper” (2, 3), a popular place of residence for microglia. Although not entirely defined, microglia’s role in immune privilege must involve these cell’s neurotrophic, de-inflammatory, and phagocytic activities, all of which help protect the brain from immune-mediated response and aid in the cleansing function of the “glymphatic system” (3,7).

However, microglia are not to be painted only as the watchers and heroes of the CNS. More emergent research has shown that in the normal developing brain microglia and other immune-related proteins play an active part in activity-dependent elimination and refining of synaptic connections. Evidence for this came in the form of presynaptic and postsynaptic elements within microglial lysosomes imaged through electron microscopy and high resolution in vivo engulfment assays (6). While in a non-pathological context, microglia generally perform a healthy and selective amount of synaptic pruning and activation, but their function can easily turn maladaptive and aggravate conditions in a pathological or dysfunctional brain (5).

Microglia-derived factors can become cytotoxic to neurons in cases of glial cell overgrowth or if secreted inappropriately. This may result in neurodegeneration or demyelination, and is possible in an autoimmune pathological context such as in multiple sclerosis (3). Recently, there has been an increasing interest in microglia’s role in neurodegenerative diseases such as Alzheimer’s. For example, CD33, a cell-surface antigen in immune cells (including microglia), inhibits uptake of Aβ42, which contributes to the onset of AD (5,6). Moreover, a variant of the gene encoding TREM2 (triggering receptor expressed on myeloid cells 2), which is highly expressed in immune cells, imparts an AD risk similar to ApoE and is known to stimulate phagocytosis and suppress inflammation (5,6). Evidence has established that microglia are involved in the refinement and wiring of the developing brain and in the regulation of CNS homeostasis and repair (3,5,6); they are a key link between the neuro and immune. Future research should focus on this link and these cells’ contribution to cases of synaptic dysfunction and neurodegeneration. Endeavors in this direction will possibly pinpoint therapeutic targets and develop ways of optimizing microglial function and their potential as a non-invasive means of delivering cell therapy to the brain.

References

1. Purves D et al. (2012) in Neuroscience (Sinauer Associates, Sunderland, MA), pp 559-561. 5th Ed.

2. Galea I, Bechmann I, Perry V (2007) What is immune privilege (not)?. Trends in Immunology 28:12-18. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17129764 [Accessed September 26, 2017].

3. Kettenmann H, Hanisch U, Noda M, Verkhratsky A (2011) Physiology of Microglia. Physiological Reviews 91:461-553. Available at: http://physrev.physiology.org/content/91/2/461.full [Accessed September 26, 2017].

4. Hanisch U, Kettenmann H (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nature Neuroscience 10:1387-1394. Available at: https://www-ncbi-nlm-nih-gov.ezproxyhost.library.tmc.edu/pubmed/?term=Microglia%3A+active+sensor+and+versatile+effector+cells+in+the+normal+and+pathologic+brain [Accessed September 26, 2017].

5. Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: New Roles for the Synaptic Stripper. Neuron 77:10-18. Available at: http://www.sciencedirect.com/science/article/pii/S0896627312011622 [Accessed September 26, 2017].

6. Hong S, Dissing-Olesen L, Stevens B (2016) New insights on the role of microglia in synaptic pruning in health and disease. Current Opinion in Neurobiology 36:128-134. Available at: http://www.sciencedirect.com/science/article/pii/S0959438815001828 [Accessed September 26, 2017].

7. Louveau A, Harris T, Kipnis J (2015) Revisiting the Mechanisms of CNS Immune Privilege. Trends in Immunology 36:569-577. Available at: https://www-ncbi-nlm-nih-gov.ezproxyhost.library.tmc.edu/pmc/articles/PMC4593064/ [Accessed September 26, 2017].

8. Del Rio-Hortega P. Microglia. In: Cytology and Cellular Pathology of the Nervous System, edited by Penfield W. New York: Hoeber, 1932, p. 482–534.

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