Microglia

Author: Christos Bozidis • Reviewer: Assist. Prof. Konstantinos Ι. Tsamis, MD
Last reviewed: March 21, 2024
Reading time: 15 minutes

Microglia are a type of glial cell which are essential for the defense mechanisms in the central nervous system (CNS). Microglia share structural and functional similarities with tissue macrophages, highlighting their role in immune responses within the CNS.

Despite belonging to glia, microglia are notably smaller and distinct from other cell types in the macroglia category, including astrocytes, oligodendrocytes, and ependymal cells. Their population is the smallest among all other cells in the CNS.

Key facts about microglia
Location	Central nervous system
Structure	Resting State: Branched processes, small cell body, with a dash-like nucleus Activated state: Larger cell body with few or no processes Phagocytic state: Enlarged cell body with lipid granules and no processes
Origin	Yolk sac erythro-myeloid precursor
Markers	- Molecules belonging to a phagocytic and antigen presenting cell phenotype - Unique microglia markers (like TMEM119, P2RY12, and SALL1)
Function	- Phagocytosis - Antigen presentation - Removal of metabolic waste products - Regulation of neurons and other glia - Response to damage, inflammation, infection, and degeneration - Nervous tissue growth, repair, and renewal

Contents

Location
Structure
Origin
Microglia markers
Function
Microglia vs Astrocyte
Clinical relations
Sources

+ Show all

Location

Microglia are exclusively located in the CNS, distributed in both gray and white matter, with a slight preference for white matter. In the human brain, higher concentrations of microglia can be found in the brainstem, hippocampus and basal ganglia, while areas with the least concentration are the cortex of the cerebellum and neocortex. Microglial cell numbers increase in response to recent trauma or inflammation, as these cells actively encircle and penetrate the affected tissues to perform their immune functions. Greater concentrations of microglia are also observed in parts of the brain tissue where there is extensive neuronal degeneration.

Structure

Microglial cells, as their name implies, are the smallest type of glial cells. Under a microscope, their small and elongated nuclei have a dash-like form, making them easily distinguishable from the larger and rounded nuclei of other cell types. The structure and appearance of microglial cells vary significantly depending on their functional state:

Resting state

In the resting state, the cell's surface features numerous short and unevenly-shaped processes branching out in various directions. These dynamic processes constantly change in length and shape, enabling the microglia to monitor their environment.

Activated state

In the activated state, the branches of microglial cells shorten and thicken, as the cell initiates vesicle and protein production. Simultaneously, the cell's body increases in size, eventually adopting an amoeboid shape with almost no visible processes, resembling a typical tissue macrophage. The microglial cell membrane in the activated state is folded, reflecting a constant state of phagocytosis and pinocytosis due to the cell's macrophagic functions. An augmented Golgi apparatus, along with numerous lysosomes and phagosomes, appears in the cytoplasm under an electron microscope.

Phagocytic state

After extended phagocytosis, microglial cells increase in size and accumulate lipid granules, adopting a distinctive appearance known as a gitter cell. This appearance is typically found in regions of the CNS experiencing infection, inflammation, or trauma.

Origin

Unlike other glial cells, microglia do not originate from the ectoderm (ventricular part of the neural tube) but instead come from the mesoderm. Microglia are part of the mononuclear phagocyte system, along with blood monocytes and all subtypes of tissue macrophages. Their phenotype suggests a common origin with monocytes in the blood, tracing back to the yolk sac erythro-myeloid precursor. This cell type differentiates into either a fetal monocyte destined for the blood vessels and peripheral tissue or a yolk sac macrophage. The latter migrates to the CNS during late embryonic life and further differentiates into primitive forms of microglia. This event occurs simultaneously with the vascularization of the CNS, specifically during the development of the blood-brain barrier by astrocytes.

Consequently, after the formation of blood vessels supplying nervous tissue, microglia are the only immune cells that have infiltrated the blood-brain barrier. Accordingly, no microglia can be observed in nervous tissue before its vascularization. Due to early-stage diversion from the typical mononuclear differentiation path, microglia do not depend on bone marrow stem cells for renewal and instead have self-renewal properties.

Microglia markers

Microglia are essentially phagocytic cells, exhibiting the phenotype of phagocytes. The majority of their membrane and intracellular proteins are shared with tissue macrophages due to their common origin. They express numerous cluster of differentiation (CD) membrane proteins (such as CD11, CD14, CD16, CD40, CD45, CD68, CD80) and ionized calcium-binding adapter molecule 1 (IBA-1), even in the resting state. Activation induces the expression of different surface markers (CD32, CD86, major histocompatibility complex class II (MHC II)) or upregulation of others (CD16, CD40, IBA-1) mainly related to phagocytosis processes and immune system regulation.

However, many of these markers are not specific to microglia and can be detected in other cells. Unique markers for microglia have been identified for distinguishing microglia from infiltrating macrophages or other glial cells for diagnostic and research purposes. Some well-known specific markers include:

Transmembrane protein 119 (TMEM119)
Purinergic receptor P2Y, G-protein coupled, 12 (P2RY12)
Sal-like protein 1 (SALL1)

Despite the existence of general microglia markers and other markers related to the current cell phenotype, there are also markers highlighting a broad spectrum of intrinsic heterogeneity within the cell population, mainly related to their localization in different brain regions.

Function

Microglia represent the only form of native active immunity in the CNS, serving as the primary defense and preservation mechanism. Notably, microglial cells are highly mobile, moving extensively throughout the neuropil—comprising nerve fibers, dendrites, glial processes, vessels, and cell bodies—constantly surveying and sweeping the nervous tissue. This unique function of microglia relies on several specific features.

Recognizing and destroying microorganisms, toxins, and other antigens

The CNS lacks connective tissue, except in restricted areas around the choroid plexi and the largest blood vessels. Consequently, a typical inflammatory response cannot occur in case of damage or infection. Microglia take on the role of producing an equivalent response. Through pattern recognition receptors (PRRs), these cells react to antigens and toxic substances, transitioning to an activated state where phagocytosis culminates. Simultaneously, they produce cytokines and cytotoxic factors such as reactive oxygen species (ROS), nitric oxide, and tumor necrosis factor (TNF).

Removing cellular metabolic waste products and damaged cell parts

Utilizing PRRs, microglia also identify useless molecules and cellular components within the neuropil and remove them, primarily through pinocytosis. This function is vital for maintaining the molecular balance in nervous tissue and organizing the microenvironment of neurons, as neuronal activity is highly sensitive to changes in the composition of the extracellular space.

Presenting antigens to lymphocytes, triggering an immune response

Apart from their role as phagocytic cells, microglia also function as antigen-presenting cells. This property is crucial for the defense of the CNS since there is no other type of antigen-presenting cell capable of crossing the intact blood-brain barrier. After connecting with and phagocytosing the antigen, the microglial cell presents it on its surface while releasing chemokines like interleukins and inflammation intermediates. Consequently, the cells communicate with lymphocytes on the other side of the blood-brain barrier, leading to their activation and subsequent infiltration into the nervous tissue to initiate an immune response.

Terminating dysfunctional or destroyed neurons

In cases of apoptosis, necrosis, or extreme stress, molecules of phosphatidylserine migrate via translocation from the inner part of the neuron's cellular membrane to the outer part. This stimulates special receptors and opsonins of the microglia, leading to the entrapment and removal of the neuron. Such a response can also be triggered by incredibly sensitive potassium channels that can sense small changes in extracellular potassium (in the case of cell necrosis, intracellular potassium gets released into the extracellular space). This process is extensive in neurodegenerative diseases and is called neuronophagia.

Supporting nervous tissue development and regeneration

In the developing brain, microglia phagocytose neural and glial progenitor cells, neurons, and oligodendrocytes, assisting in proper circuit formation, axonal myelination, and differentiation. Microglial cells also contact neuronal somata, modulating their activity and nurturing neurons. They play a role in removing toxic waste, releasing anti-inflammatory factors, and pruning ineffective synapses, thereby sculpting neuronal circuits. These properties contribute to neuronal plasticity, tissue renewal, and repair in the adult CNS, as well.

Responding to tissue damage

Due to the absence of connective tissue, in cases of extensive damage in the CNS, the observed reaction differs from typical scar tissue formation. Instead, astrocytes in the damaged area release transforming growth factor-β (TGF-β) and other signaling molecules, which activate and attract microglia. Microglial cells proliferate and migrate to the damaged area. After a few hours, the damaged tissue becomes crowded with activated microglia that further proliferate, forming nodules, releasing cytokines, and initiating phagocytosis and the secretion of cytotoxic factors.

Microglia vs Astrocyte

Microglia and astrocytes exhibit notable differences in structure, function, and origin, but they also share some morphological and functional characteristics. Here are key points for understanding the similarities and differences between these two cell types:

Cell body size: The cell bodies of microglia are smaller than those of astrocytes.
Nuclear morphology: Microglial cells have dash-like nuclei, contrasting with the rounded nuclei of astrocytes.
Processes: Both cell types have processes that branch out, but microglial processes are much shorter and more extensively branched than those of astrocytes. Reactive astrocytes may resemble microglia in certain pathological cases, but their cell bodies are generally larger.
Distribution in nervous tissue: Microglial cells are scattered throughout the nervous tissue, while astrocytes are typically found surrounding blood vessels, contributing to the formation of the blood-brain barrier.
Mobility: Microglial cells are highly mobile and can be found in random locations between surrounding nerve fibers. In contrast, astrocytes are mainly located with their processes attached to blood vessels or supporting synapses.
Activation in Response to Injury, Disease, and Infection: Both microglial cells and astrocytes can be activated in response to injury, disease, and infection. Reactive astrocytes primarily participate in signaling pathways and may replace damaged neurons (astrogliosis). Activated microglia, in contrast, play a significant role in phagocytosis, removing damaged tissue and microbes from the affected area.

Clinical relations

Microglia activation and migration into damaged areas can be detrimental in certain pathologies, where overactivation of microglia may result in excessive neurotoxicity. Additionally, the heightened secretion of cytokines by microglia can lead to increased blood vessel permeability, causing the rupture of the blood-brain barrier and disrupting the microenvironment of neurons. The upregulated receptors in these scenarios belong to the group of pattern recognition receptors (PRRs), which bind to molecules known as pathogen-associated molecular patterns (PAMPs). Examples include beta-amyloid in Alzheimer's disease, alpha-synuclein in Parkinson's disease, and antigens of neurotropic viruses.

Astrocytes are also affected by activated microglial cells and enter a reactive state that may be detrimental to neuronal activity and blood-brain barrier permeability in the long run. Consequently, microglia appear to be involved in the pathological cascade of neurodegenerative diseases, although their actual role as neuroprotective or neurotoxic factors remains controversial.

Sources

All content published on Kenhub is reviewed by medical and anatomy experts. The information we provide is grounded on academic literature and peer-reviewed research. Kenhub does not provide medical advice. You can learn more about our content creation and review standards by reading our content quality guidelines.

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