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Microglial cell origin and phenotypes in health and disease

Key Points

  • In the central nervous system, microglia have important roles in maintaining tissue homeostasis and responding to infection and injury.

  • Microglia in the brain parenchyma originate from primitive macrophages in the yolk sac and form a population that is distinct from bone marrow-derived macrophages.

  • Microglia can exhibit distinct phenotypes depending on context. These include a quiescent phenotype under normal conditions, a 'classically activated' phenotype in the setting of infection and injury, and an 'alternatively activated' phenotype that is associated with brain tumours.

  • A mild form of a classically activated microglial cell phenotype is frequently observed in the context of chronic neurodegenerative diseases and may be associated with the production of neurotoxic mediators.

  • Alternatively activated microglia are associated with gliomas and are characterized by an immunosuppressive phenotype and the production of mediators that support tumour invasion.

  • Mechanisms that maintain a quiescent phenotype under normal conditions and promote the resolution of classical activation states are regulated by cell–cell communication with neurons and other glial cells, by anti-inflammatory cytokines and by endogenous hormones that are generated locally within the CNS and act by regulating nuclear hormone receptors.

Abstract

Microglia — resident myeloid-lineage cells in the brain and the spinal cord parenchyma — function in the maintenance of normal tissue homeostasis. Microglia also act as sentinels of infection and injury, and participate in both innate and adaptive immune responses in the central nervous system. Microglia can become activated and/or dysregulated in the context of neurodegenerative disease and cancer, and thereby contribute to disease severity. Here, we discuss recent studies that provide new insights into the origin and phenotypes of microglia in health and disease.

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Figure 1: Relationship of microglia to myeloid-lineage cells.
Figure 2: Steady-state and alternatively activated microglial cell phenotypes.
Figure 3: Classically activated microglia participate in both innate and adaptive immune responses.
Figure 4: Classically activated microglia in neurodegenerative disease.
Figure 5: Deactivation of classically activated microglia.

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Acknowledgements

The authors thank C. Benner for analysis of publicly available gene expression data. We apologize to colleagues for not citing all relevant papers because of limited space.

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Correspondence to Christopher K. Glass.

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FURTHER INFORMATION

BioGPS

Glossary

Astrocytes

Glial cells that are found in vertebrate brain and are named for their characteristic star-like shape. These cells provide both mechanical and metabolic support for neurons, thereby regulating the environment in which they function.

Oligodendrocytes

Glial cells that create the myelin sheath that insulates axons and improves the speed and reliability of signal transmission by neurons.

Alzheimer's disease

The most common type of neurodegenerative dementia. Patients often have impairments in learning and memory. The neuropathology of the disease includes neuron loss in the cerebral cortex and in some subcortical regions, and the presence of aggregates in the form of senile plaques (which contain amyloid-β) and neurofibrillary tangles (which contain hyperphosphorylated tau).

Blood–brain barrier

A barrier formed by tight junctions between endothelial cells that markedly limits entry to the central nervous system by leukocytes and all large molecules, including to some extent immunoglobulins, cytokines and complement proteins.

Type 2 diabetes mellitus

(T2D). A disorder of glucose homeostasis that is characterized by inappropriately increased blood glucose levels and the resistance of tissues to the action of insulin. Recent studies indicate that inflammation in adipose tissue, liver and muscle contributes to the insulin-resistant state that is characteristic of T2D, and that the anti-diabetic actions of peroxisome proliferator-activated receptor-γ agonists result, in part, from their anti-inflammatory effects in these tissues.

Amyotrophic lateral sclerosis

A neurodegenerative disorder that affects the motor neurons in the brain.

Amyloid precursor protein

(APP). A membrane glycoprotein component of the fast axonal transport machinery, from which amyloid-β is cleaved by proteolytic processing.

Presenilin 1

A transmembrane protease that has an active site in the plane of the membrane and can therefore cleave transmembrane peptides. Mutations of the presenilin 1 gene are associated with early onset Alzheimer's disease.

Tau

A neuronal protein that binds to microtubules, promoting their assembly and stability.

Tumour-associated macrophages

An important component of the tumour microenvironment. These cells differentiate from circulating blood monocytes that have infiltrated tumours. They can have positive or negative effects on tumorigenesis (that is, tumour promotion or immunosurveillance, respectively).

High-mobility group box 1

(HMGB1; also known as amphoterin). A nuclear protein that binds DNA in a non-sequence-specific manner and modulates transcription and chromatin remodelling by bending DNA and facilitating the binding of transcription factors and nucleosomes.

Amyloid-β

A peptide of 39–43 amino acids that is the main constituent of amyloid plaques in the brains of patients with Alzheimer's disease. These plaques are composed of a tangle of regularly ordered fibrillar aggregates called amyloid fibres. Among these heterogeneous peptide molecules, amyloid-β1–40 and amyloid-β1–42 are the most common isoforms. Amyloid-β1–42 is the most fibrillogenic peptide and is thus associated with disease states.

Substantia nigra

A structure located in the midbrain that is important in reward behaviour, addiction and movement. Parkinson's disease is caused by the death of dopaminergic neurons in the substantia nigra.

α-synuclein

A neuronal protein of unknown function that is detected mainly in presynaptic terminals. It can aggregate to form insoluble fibrils known as Lewy bodies, which are observed in pathological conditions such as Parkinson's disease.

Astrogliosis

An increase in the number of astrocytes owing to proliferation at sites of damage in the central nervous system.

Neurofibrillary tangles

Pathological protein aggregates found in the neurons of patients with Alzheimer's disease. Tangles are formed through hyperphosphorylation of the microtubule-associated protein tau, causing it to aggregate in an insoluble form.

Apolipoprotein E

A key protein constituent of certain lipoproteins and a ligand for hepatic receptors.

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Saijo, K., Glass, C. Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11, 775–787 (2011). https://doi.org/10.1038/nri3086

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