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Innate immunity: the missing link in neuroprotection and neurodegeneration?

Nature Reviews Neuroscience volume 3, pages 216–227 (2002)Cite this article

Key Points

  • The central nervous system mounts an innate immune response during systemic infection. This inflammatory response is characterized by the expression of Toll-like receptors (TLRs) in structures that are devoid of blood–brain barrier. The response extends progressively to affect microglia across the brain parenchyma, and might lead to the onset of an adaptive immune response.

  • Molecules of both innate and adaptive immune systems are induced in several neurological disorders, and it has been proposed that immunological challenges might act as aetiological factors in sporadic cases of neurodegeneration, perhaps through the recognition of neuronal fingerprints, or after an inflammatory reaction that is elicited by peripheral stimuli.

  • Chronic stimulation of the innate immune response by microglia might directly cause neuronal death. In addition, by stimulating the production of pro-inflammatory molecules, this response might also promote leakage across the blood–brain barrier and the subsequent establishment of an adaptive immune response.

  • In addition to its potentially detrimental role, the innate immune response can also have a beneficial effect. Indeed, this immune response can protect neurons by favouring remyelination and trophic support afforded by glial cells.

Abstract

Innate immunity was previously thought to be a nonspecific immunological programme that was engaged by peripheral organs to maintain homeostasis after stress and injury. Emerging evidence indicates that this highly organized response also takes place in the central nervous system. Through the recognition of neuronal fingerprints, the long-term induction of the innate immune response and its transition to an adaptive form might be central to the pathophysiology and aetiology of neurodegenerative disorders. Paradoxically, this response also protects neurons by favouring remyelination and trophic support afforded by glial cells.

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Figure 1: The family of TLRs and pro-inflammatory signal-transduction pathways that recruit NFκB.
Figure 2: Response wave of TLR2-expressing cells across the mouse brain to bacterial endotoxin LPS.
Figure 3: Autocrine and paracrine roles of TNF-α in the synthesis of CD14 in microglial cells during endotoxaemia.
Figure 4: Potential beneficial roles of pro-inflammatory cytokines during the innate immune reaction.
Figure 5: Hypothetical mechanism of selective neurodegeneration involving components of innate and adaptive immunity.

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Acknowledgements

Our work is supported by the Canadian Institutes of Health Research (CIHR) and the Neuromuscular Research Partnership. M.D.N. is a recipient of a K. M. Hunter–CIHR Ph.D. Scholarship. J.-P.J. holds a CIHR Senior Investigator Award. S.R. is a CIHR Scientist and holds a Canadian Research Chair in Neuroimmunology. We thank G. Chabot, S. Nadeau and N. LaFlamme for assistance with the illustrations.

Author information

Authors and Affiliations

  1. Centre for Research in Neurosciences, McGill University, The Montréal General Hospital Research Institute, Montréal, H3G 1A4, Québec, Canada

    Minh Dang Nguyen & Jean-Pierre Julien

  2. Laboratory of Molecular Endocrinology, CHUL Research Center and Laval University, 2705 Boulevard Laurier, Sainte-Foy, G1V 4G2, Québec, Canada

    Serge Rivest

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  1. Minh Dang Nguyen
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  2. Jean-Pierre Julien
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Correspondence to Serge Rivest.

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DATABASES

FlyBase

Toll

 LocusLink

CD14

GABAA receptor γ2

GluR3

glycine receptor α2

Iba1

IFN-γ

IKAP

IκB

IKK

IL-1

IL-1R

IL-12

IRAK

Munc-18

MyD88

NFκB

NIK

NOVA1

RIP

TLRs

TNF-α

TNFR1

TNFR2

TRADD

TRAF2

TRAF6

 OMIM

ALS-parkinsonism/dementia complex of Guam

Alzheimer's disease

amyotrophic lateral sclerosis

frontotemporal dementia

Huntington's disease

multiple sclerosis

Parkinson's disease

stiff-man syndrome

 PROSITE

TIR domain

FURTHER INFORMATION

antigen presentation to lymphocytes

blood–brain barrier

microglia

nervous and immune system interactions

neuroimmunology

Glossary

INNATE IMMUNITY

The early response of a host to infection. One of its main features is the pro-inflammatory response induced by antigen-presenting cells — macrophages, dendritic cells and, in the brain, microglial cells. This response is followed by an adaptive response that is mediated by the clonal selection of lymphocytes, which leads to long-term immune protection.

CIRCUMVENTRICULAR ORGANS

Brain regions that have a rich vascular plexus with a specialized arrangement of the blood vessels. The junctions between the capillary endothelial cells are not tight in the blood vessels of these regions, allowing the diffusion of large molecules. These organs include the organum vasculosum of the lamina terminalis, the subfornical organ, the median eminence and the area postrema. Although not included as circumventricular organs, the choroid plexus and leptomeninges are also highly vascularized and are rapidly activated by circulating pathogens.

ADAPTIVE IMMUNITY

Also known as acquired immunity, it describes the response of antigen-specific lymphocytes to antigen and the development of immunological memory. It is mediated by the clonal selection of lymphocytes.

STIFF-MAN SYNDROME

A neuromuscular disorder that is characterized by progressive rigidity and a hyperactive startle reflex that results in the contraction of muscles, causing violent spasms.

RASMUSSEN ENCEPHALITIS

A childhood disease that is characterized by seizures, hemiparesis, inflammation and mental deterioration.

PATHOGEN-ASSOCIATED MOLECULAR PATTERNS

Specific elements that are produced by microorganisms and can induce innate immune responses. These elements are recognized by specific receptors that are expressed at the surface of macrophages, dendritic cells and microglia.

GRAM-NEGATIVE BACTERIA

Bacteria that do not retain a basic blue dye during the Gram-stain procedure. Their cell walls are thin, consisting of a layer of lipopolysaccharide outside a peptidoglycan layer.

GRAM-POSITIVE BACTERIA

Bacteria that retain a basic blue dye during the Gram-stain procedure. Their cell wall is thicker than that of Gram-negative bacteria, containing more peptidoglycan.

NUCLEAR FACTOR κB

A family of transcription factors that are important for pro-inflammatory and anti-apoptotic responses.

CYTOKINES

In general terms, cytokines are proteins made by cells that affect the behaviour of other cells. They are produced mainly by the immune system.

TOLL-LIKE RECEPTORS

A large family of receptors that are expressed at the surface of leukocytes and microglial cells. They are responsible for engaging the innate immune system in response to pathogens.

ANTIGEN-PRESENTING CELLS

Specialized cells that present specific antigens to T cells. Macrophages and dendritic cells are the main antigen-presenting cells; in the CNS, the antigen-presenting cells are the microglia.

DEATH DOMAIN

A protein–protein interaction domain found in many proteins that are involved in signalling and apoptosis.

CHEMOKINES

Small, secreted proteins that stimulate the motile behaviour of leukocytes.

COMPLEMENT SYSTEM

A set of plasma proteins that attack extracellular pathogens. The pathogen becomes coated with complement proteins that facilitate pathogen removal by phagocytes.

CD14

The first lipopolysaccharide receptor to be characterized. It exists two forms: membrane CD14 (mCD14) and soluble CD14 (sCD14). mCD14 is present at the surface of myeloid cells and acts as a glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein, whereas sCD14 lacks the GPI anchor, but can bind LPS to activate cells that are devoid of mCD14, such as endothelial cells.

CHOROID PLEXUS

A site of production of cerebrospinal fluid in the adult brain. It is formed by the invagination of ependymal cells into the ventricles, which become richly vascularized.

DENDRITIC CELLS

Also known as interdigitating reticular cells because of their branched morphology, dendritic cells are the most potent stimulators of T-cell responses.

LEPTOMENINGES

The pia mater and the arachnoid considered together.

TNF-α

Tumour necrosis factor-α. A cytokine produced by macrophages that has multiple functions in the immune response.

EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS

A rodent model of multiple sclerosis that is characterized by episodes of spasticity and tremor.

OPSONIZATION

The alteration of the surface of a pathogen so that it can be ingested by a phagocyte.

HELPER T CELLS

At least two distinct subsets of activated CD4+ T lymphocytes have been described. TH1 cells produce IFN-γ, lymphotoxin and TNF-α, and support cell-mediated immunity. TH2 cells produce IL-4, IL-5 and IL-13, support humoural immunity, and downregulate TH1 responses.

FAS

A transmembrane protein that mediates apoptosis and might be involved in the negative selection of autoreactive T cells in the thymus.

CASPASES

Cysteine proteases involved in apoptosis, which cleave at specific aspartate residues.

PROSTAGLANDINS

Biologically active metabolites of arachidonic acid and other lipids. Prostaglandins have many functions; for example, they are involved in vasodilation, bronchodilation, inflammatory reactions and the regulation of cell proliferation. They are also involved in the control of endocrine functions.

CYCLIN-DEPENDENT KINASES

Enzymes that phosphorylate proteins that are involved in DNA synthesis and mitosis. They require a cyclin partner for activity and substrate specificity.

BCL PROTEINS

Molecules that are associated with B-cell leukaemia and lymphoma. Bcl2 is a mitochondrial protein of the inner membrane that can block apoptosis.

MAJOR HISTOCOMPATIBILITY COMPLEX

There are two classes of MHC molecules. MHC class I molecules are found on the surface of most cells and present proteins that are generated in the cytosol to T lymphocytes. MHC class II molecules are expressed only at the surface of activated antigen-presenting cells, and they present peptides that have been degraded in cellular vesicles to T cells.

FINGERPRINT

A distinct set of proteins expressed by a given population of neurons, which might account for the specialized biochemical properties of these neurons, and make them vulnerable to an immune challenge by acting as antigens.

PARANEOPLASTIC NEUROLOGICAL DISEASES

A set of neurodegenerative disorders that arise in the context of cancer and are believed to be mediated by the immune system. Patients harbour autoantibodies that are targeted to specific tumour and neuronal antigens (onconeural antigens).

ALTERNATIVE SPLICING

During splicing, introns are excised from RNA after transcription and the cut ends are rejoined to form a continuous message. Alternative splicing allows the production of different messages from the same DNA molecule.

GEPHYRIN

A cytosolic protein that clusters glycine and GABAA receptors at synapses.

AMPHIPHYSIN

A molecule located at the presynaptic terminal that interacts with several proteins that are important in the synaptic-vesicle cycle.

SUPPRESSOR T CELLS

Lymphocytes that can suppress the activity of naive or effector T cells. They produce TGF-β, which inhibits T-cell proliferation.

CYTOTOXIC T CELLS

Lymphocytes that can kill other cells and are important in host defence against cytosolic pathogens. They are commonly MHC class I CD8 cells.

CD4/CD8 RATIO

Most T lymphocytes express one of two antigens — CD4 and CD8. CD4 is expressed by helper and inflammatory T cells and is a co-receptor for MHC class II molecules. CD8 is expressed by cytotoxic T cells and is a co-receptor for MHC class I molecules. An increased CD4/CD8 ratio commonly indicates heightened immune function, whereas a decreased ratio is indicative of prevalent disease.

ISCHAEMIC PENUMBRA

A term that is generally used to define ischaemic but still viable cerebral tissue that surrounds a core ischaemic zone.

HAEMORRHAGIC TRANSFORMATION

Secondary bleeding that can occur after an ischaemic episode.

PROGRESSIVE SUPRANUCLEAR PALSY

A brain disorder that affects the control of gait and balance. The most obvious sign of the disease is an inability to direct the eyes properly, reflecting lesions in brainstem regions that coordinate eye movements. Patients often show alterations of mood and behaviour, including depression, apathy and mild dementia.

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Nguyen, M., Julien, JP. & Rivest, S. Innate immunity: the missing link in neuroprotection and neurodegeneration?. Nat Rev Neurosci 3, 216–227 (2002). https://doi.org/10.1038/nrn752

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