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  • Review Article
  • Published:

Regulation of innate immune responses in the brain

Nature Reviews Immunology volume 9, pages 429–439 (2009)Cite this article

Key Points

  • Microglial cells are highly ramified cells and their cell processes are active and plastic even during normal conditions. Similar to macrophages, microglial cells express Toll-like receptors (TLRs) and can respond to TLR ligands by the production of pro-inflammatory mediators. They are the main innate immune cells of the central nervous system (CNS).

  • These cells can be activated during systemic infections without the integrity of the blood–brain barrier (BBB) being compromised. Some regions of the brain have no BBB, known as the circumventricular organs, and the response to circulating pathogens at these sites is similar to that in most systemic organs.

  • A robust inflammatory response occurs in the cerebral tissue of mouse models of herpes simplex virus (HSV) encephalitis. The inflammatory response is initially required to restrict the first stages of viral replication, but this response must be subsequently suppressed to avoid severe neuronal damage. By contrast, infiltration of leukocytes into the CNS is a crucial process in both the vulnerability to (through TLR3 and the chemokine CCL2) and defence against (through TLR7) West Nile virus encephalitis in mice.

  • The activation of innate immune signalling pathways in microglial cells not only occurs in response to infectious organisms, but also during brain injury and chronic disease. It remains highly debated whether such a response has neuroprotective or neurodestructive effects.

  • Acute administration of lipopolysaccharide (LPS) modulates the expression of key genes involved in the recruitment and differentiation of oligodendrocyte progenitor cells and in oligodendrocyte-mediated remyelination. In contrast to these beneficial effects of LPS in the adult brain, the activation of TLRs is toxic to oligodendrocytes in developing brains.

  • Receptors of the innate immune system are involved in the removal of amyloid-β (Aβ) in the brain. Indeed, the Aβ load is modulated in part by TLR2 and TLR4, and activation of TLR2, TLR4 and TLR9 increases the uptake of Aβ by microglial cells in the brains of mouse models of Alzheimer's disease.

  • Bone marrow-derived microglial cells have been shown to be closely associated with Aβ plaques and to slow the progression of the disease by removing Aβ from the CNS. Moreover, blocking the transforming growth factor-β-induced signalling pathway in peripheral macrophages and systemic administration of macrophage colony-stimulating factor improved Alzheimer's disease-like pathology.

  • A better understanding of the innate immune response in the cerebral tissue will help us to develop innovative strategies to activate microglial cells more effectively whilst avoiding detrimental effects on the neuronal elements. In this regard, the development of new synthetic and pure TLR agonists is required to stimulate these innate immune cells specifically towards neuroprotective functions.

Abstract

Microglial cells are the main innate immune cells of the complex cellular structure of the brain. These cells respond quickly to pathogens and injury, accumulate in regions of degeneration and produce a wide variety of pro-inflammatory molecules. These observations have resulted in active debate regarding the exact role of microglial cells in the brain and whether they have beneficial or detrimental functions. Careful targeting of these cells could have therapeutic benefits for several types of trauma and disease specific to the central nervous system. This Review discusses the molecular details underlying the innate immune response in the brain during infection, injury and disease.

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Figure 1: Expression of Toll-like receptor 2 (Tlr2) mRNA in the mouse brain.
Figure 2: Inhibition of pro-inflammatory signalling by glucocorticoids.
Figure 3: Amyloid-β cleavage pathways.
Figure 4: Blood-derived microglial cells as a cure for neurodegenerative diseases.
Figure 5: Dual nature of the innate immune response in the central nervous system.

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Acknowledgements

The Canadian Institutes in Health Research (CIHR) and Neuroscience Canada (Brain Repair Program) support this research. S.R. holds a Canadian Research Chair in Neuroimmunology. The author is grateful to D. Soulet, I. Glezer and M.M. Plante for the original graphical illustrations.

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  1. and Department of Anatomy and Physiology, Laboratory of Endocrinology and Genomics, Centre Hospitalier Universitaire de Québec Research Center (CHUL), Laval University, 2705 Laurier Boulevard, Québec, G1V 4G2, Canada

    Serge Rivest

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DATABASES

OMIM

Alzheimer's disease

Glossary

Microglial cell

A phagocytic cell of myeloid origin that is involved in the innate immune response in the central nervous system. Microglial cells are thought to be brain-resident macrophages.

Toll-like receptor

(TLR). A type of pattern recognition receptor that recognizes unique structures derived from microorganisms. Signalling through TLRs promotes inflammatory immune responses, cytokine production and cell activation in response to microorganisms.

Blood–brain barrier

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

Choroid plexus

A capillary bed that is covered by transporting ependymal cells and that protrudes into the cerebral ventricles. The ependymal cells produce cerebrospinal fluid.

Leptomeninges

The pia mater and the arachnoid mater considered together.

Astrocyte

A star-shaped glial cell of the central nervous system that forms a structural and functional interface between non-nervous tissues and neurons.

Multiple sclerosis

A chronic inflammatory and demyelinating disease of the central nervous system. Multiple sclerosis involves an autoimmune response against components of myelin, which is thought to contribute to disease pathogenesis.

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 plaques (containing amyloid-β) and neurofibrillary tangles (containing hyperphosphorylated tau).

Ischaemic injury

Damage to neurons that results from a deficiency in the blood supply to that region of the brain, owing to functional constriction or physical obstruction of a blood vessel. Ischaemic stroke is an episode of acute regional ischaemia in the brain, usually caused by thrombi or emboli from atherosclerotic plaques, that leads to the death of nerve cells.

Cross-tolerance

A transient state of hyporesponsiveness of host antigen-presenting cells to other TLR ligands after previous exposure to a TLR ligand.

Glucocorticoids

A group of compounds that belongs to the corticosteroid family. These compounds can be naturally produced (hormones) or synthetic. They affect metabolism and have anti-inflammatory and immunosuppressive effects. Some synthetic glucocorticoids (for example, dexamethasone) are used as chemotherapeutic drugs.

Substantia nigra

A part of the midbrain that contains dopamine-producing neurons.

Oligodendrocyte progenitor cell

The progenitor of oligodendrocytes in the CNS. The progenitor cells are generated in restricted, stem cell-containing regions of the CNS, from where they migrate to the axon tracts that become myelinated.

Oligodendrocyte

A type of glial cell that produces the myelin sheath that insulates axons and improves the speed and reliability of signal transmission by neurons.

Myelination

The formation of an insulating layer (that is, a myelin sheath) around a nerve fibre or axon to increase the speed at which action potentials are conducted.

Cerebrospinal fluid

A liquid that is produced by ependymal cells of the choroid plexus, which thereafter circulates in the cerebroventricular system.

Senile plaque

A site of amyloid-β accumulation and damaged neurons in the brains of mouse models and patients with Alzheimer's disease.

Inflammasome

A molecular complex of several proteins that upon assembly cleaves pro-IL-1β, thereby producing active IL-1β.

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Rivest, S. Regulation of innate immune responses in the brain. Nat Rev Immunol 9, 429–439 (2009). https://doi.org/10.1038/nri2565

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