Microglial Cells: Microglia Function, Origin and Related Conditions

The central nervous system (CNS) has its own resident and dedicated battalion of immune cells, called microglial cells. However, they are far more than just immune cells and are critical in the health, development and homeostasis of the CNS.

In this article, we consider what microglial cells are, how they are generated, their function in the body and medical conditions related to them.

What are microglial cells?

Microglial cells are a component of the immune system, but unlike other immune cells, they are uniquely located within the CNS. First described as microglial cells by the Spanish neuroscientist Pío del Río-Hortega between 1919 and 1921,^1,2 they are professional macrophages that have been shown to have multiple functions, including in; the immune response to invading pathogens, neural development, neural tissue homeostasis, inflammation and repair and regeneration.

Microglial cells comprise around 5–12% of all the cells resident in the central nervous system.³ The morphology of microglia varies depending on their activation state and their environment. In their resting state (also known as ramified), they typically have a small cell body with numerous fine processes that extend outwards, which are highly dynamic and can change in length and shape as the microglia survey their environment.

When they become activated (activated microglia) in response to injury, infection or other stimuli, the processes retract and the overall morphology of the cell changes, becoming more ameboid in shape.

While this very simplified description of microglial morphology is correct, it must be noted that as more research is done, the number of different types of microglial cell morphology identified is increasing and depends on what is stimulating them and the function they are performing.⁴

Microglial progenitor cells are derived from primitive hematopoietic stem cells in the yolk sac during early embryonic development during the third week of human gestation (Figure 1).⁵ These progenitor cells migrate from the yolk sac into the developing CNS during weeks 4–24 of gestation, where they proliferate and differentiate into mature microglial cells.⁶ Once microglial progenitor cells have colonized the CNS, they undergo further maturation and differentiation to become fully functional microglial cells.

Microglia persist throughout life as self-renewing cells, capable of proliferation and replacement in the adult CNS. They are relatively long-lived, with an estimated lifespan of 4.2 years and renew at a median rate of 28% per annum.⁷

Figure 1: Diagram showing the development of microglial cells during gestation. Credit: Technology Networks.

Microglia function

Microglial cells are critical for the maintenance of CNS homeostasis, immune responses and neural functions. They are highly dynamic, continuously moving throughout the CNS and monitoring their surroundings, enabling them to respond rapidly to any signs of infection, injury or inflammation. Some of their functions are shown in Figure 2 and include:

1. Phagocytosis: Microglia are highly motile macrophages capable of phagocytosis and scan the CNS environment for potential threats. They can engulf and digest cellular debris, dead cells, pathogens and other foreign substances. This function is essential for maintaining CNS homeostasis by removing waste and participating in tissue repair processes.⁸
   
   
2. Immune response: An integral part of CNS immune defense, they detect and respond to pathogens, injury or inflammation by becoming activated. Activated microglia release various signaling molecules (cytokines and chemokines) and reactive oxygen species, which can promote inflammation and recruit other immune cells to the site of injury, particularly T cells.⁹
   
   
3. Synaptic maintenance: Microglia play a critical role in synaptic maintenance and remodeling. During development and in the adult brain, they participate in the process of synaptic pruning, which involves the elimination of weak or unnecessary synaptic connections. This activity helps to refine neural circuits and optimize brain function.¹⁰ Additionally, they communicate with astrocytes in the maintenance of brain homeostasis.¹¹
   
   
4. Neuroprotection: They have neuroprotective functions, secreting neurotrophic factors that support the survival and growth of neurons, as well as anti-inflammatory molecules that help to resolve inflammation and prevent tissue damage.¹²
   
   
5. Remyelination: Remyelination of the CNS after injury is supported by microglia through the secretion of growth factors, clearance of debris by phagocytosis and modulation of the extracellular matix.¹³

Figure 2: Microglial cell functions. Credit: Technology Networks.

Microglial cell-related conditions

With all of our knowledge of the diverse functions of microglial cells, it is not surprising that when things go wrong they can have catastrophic consequences. Dysregulation of microglial function has been implicated in various disorders, some of which are described below.

1. Neurodegenerative conditions: In chronic neurodegenerative diseases, microglia may undergo a morphological change known as dystrophy. They display abnormal morphologies, such as fragmented processes and swollen cell bodies, and are often associated with the presence of pathological protein aggregates. Examples of these conditions are:
   
   • Alzheimer's disease (AD): Microglial activation and chronic neuroinflammation have been observed in the brains of individuals with AD, contributing to disease progression. The disease is defined by β-amyloid-containing plaques and tau-containing neurofibrillary tangles.¹⁴
   
   • Parkinson's disease (PD): Microglial activation and inflammatory responses due to the accumulation of α-synuclein have been implicated in the degeneration of dopaminergic neurons in PD.¹⁵
   
   •  Amyotrophic lateral sclerosis (ALS): ALS is characterized by extensive motor neuron loss leading to paralysis and premature death. Most cases of ALS are sporadic, but a familial component is seen in 5–10% of cases. Microglia (amongst other cells) have been implicated in the disease progression.^16,17
   
   •  Frontotemporal dementia (FTD): FTD is a group of conditions characterized by progressive nerve loss in the frontal lobes of the brain causing altered behavior, personality and language dysfunction. There is considerable genetic and pathological overlap between FTD and ALS and microglial cell dysfunctions have been implicated in both conditions.¹⁷
   
   •  Huntington's disease (HD): HD is an autosomal dominant disease of the brain with a CAG trinucleotide-encoding expansion in the Huntingtin gene. Dysregulated microglial activation and inflammatory responses have been shown to be associated with the pathogenesis of HD.¹⁸
   
   
2. Multiple sclerosis (MS): MS is a chronic inflammatory autoimmune disease of the CNS. Microglial cells, along with macrophages, participate in the inflammatory responses and demyelination seen in MS lesions, contributing to tissue damage and neuroinflammation in the CNS of MS patients.¹⁹ Microglial activation and inflammatory responses have also been implicated in other autoimmune diseases of the CNS, including autoimmune encephalitis and neuromyelitis optical.
   
   
3. Stroke: Microglial activation occurs rapidly following ischemic stroke and plays a dual role in both exacerbating tissue damage through inflammation and promoting tissue repair and remodeling.²⁰
   
   
4. Neuropsychiatric disorders: Emerging evidence suggests that microglial dysfunction and neuroinflammation may contribute to the pathophysiology of certain neuropsychiatric disorders, including depression, schizophrenia and bipolar disorder.²¹

In summary, microglial cells are crucial in the maintenance of CNS health and function, participating in immune responses, tissue repair processes and synaptic remodeling. Dysregulation of microglial activity has been implicated in a variety of conditions associated with the CNS, including neurodegenerative diseases like AD and PD, as well as neuroinflammatory disorders such as MS, tissue repair following injury and some neuropsychiatric disorders.

Further research will undoubtedly implicate them in other conditions and may well lead to further therapeutic interventions to help in some of the most insidious conditions known to science.