Microglia

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:

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.

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.