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The central nervous system (CNS) mounts an
organized INNATE IMMUNE RESPONSE during systemic bac-
terial/viral infection. This inflammatory response
is characterized by the expression ofvarious immuno-
logical proteins in the CIRCUMVENTRICULAR ORGANS
(CVOs) and other structures devoid of blood–brain
barrier (BBB).The response extends progressively to
affect microglia across the brain parenchyma and may
lead to the onset of an ADAPTIVE IMMUNE RESPONSE.
Molecules of both the innate and adaptive immune
responses are induced in a wide diversity ofneurologi-
cal disorders, including Alzheimer’s disease,
Parkinson’s disease,Huntington’s disease,multiple
sclerosisand amyotrophic lateral sclerosis(ALS).The
recent discovery ofthis immune response in the brain
revives the idea that immunological challenges might
be aetiological factors in sporadic cases of neuro-
degeneration,and indicates that primary causes ofsuch
degeneration could originate outside the CNS.Indeed,
the mechanisms that underlie 90% of ALS cases,
sporadic Parkinson’s disease and Alzheimer’s disease
remain elusive,and bacterial/viral infections have been
proposed as a primary cause.Furthermore,peripheral
antibodies generated by damaged peripheral tissues in
neurological conditions that include STIFF-MAN SYNDROME
and RASSMUSSEN ENCEPHALITIScan induce neuronal death
by targeting specific antigens.
Progress in the use ofanti-inflammatory therapies
and immunization in animal models ofneurodegener-
ative disorders points to the importance ofthe immune
response in neurodegeneration.Whereas regulation of
the innate immune response could be decisive in the
development ofboth sporadic and familial forms of
neurological disorders,molecules ofthe innate immune
response can also trigger the production of neuro-
trophic factors,and promote repair and remyelination
in response to injury, trauma and toxin-induced
demyelination.Here,we review the mechanisms that
underlie the dichotomous role of the inflammatory
response ofthe brain,a response that can,on the one
hand,protect neurons and,on the other,be a direct
Host organisms detect the presence ofinfection by recog-
nizing specific elements produced by microorganisms1.
These elements — the so-called PATHOGEN-ASSOCIATED
MOLECULAR PATTERNS(PAMPs) — are recognized by spe-
cific cells ofthe immune system as inducers ofinnate
responses to bacterial infection.The reaction to endo-
toxin lipopolysaccharide (LPS),an important com-
ponent of the outer membranes of GRAM-NEGATIVE
BACTERIA,is the best-characterized example of innate
recognition that leads to a robust inflammatory
INNATE IMMUNITY:THE MISSING
LINK IN NEUROPROTECTION AND
Minh Dang Nguyen*,Jean-Pierre Julien* and Serge Rivest‡
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.
The early response ofa host to
infection.One ofits main
features is the pro-inflammatory
response induced by antigen-
presenting cells —
and,in the brain,microglial
cells.This response is followed
by an adaptive response that is
mediated by the clonal selection
oflymphocytes,which leads to
long-term immune protection.
*Centre for Research in
General Hospital Research
and Laval University,
2705 Boulevard Laurier,
Correspondence to S.R.
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Brain regions that have a rich
vascular plexus with a
specialized arrangement ofthe
blood vessels.The junctions
between the capillary endothelial
cells are not tight in the blood
vessels ofthese regions,allowing
the diffusion oflarge molecules.
These organs include the
organum vasculosum ofthe
subfornical organ,the median
eminence and the area
included as circumventricular
organs,the choroid plexus and
leptomeninges are also highly
vascularized and are rapidly
activated by circulating
multiple leucine-rich repeats,whereas TLR cytoplasmic
domains are similar to the cytoplasmic portion ofthe
interleukin 1 (IL-1) receptor (IL-1R),commonly known
as Toll/IL-1R homologous regions (TIR domains)1,3,4.
Distinct TLRs have been proposed as key molecules in the
selective recognition ofthe main PAMPs that are pro-
duced by either Gram-negative or Gram-positive bacteria
(FIG.1).The observations that mutations ofthe mouse Lps
locus abolish the response to LPS,and that this locus
encodes TLR4,provided the first evidence that this partic-
ular receptor might be involved in the innate immune
response to Gram-negative bacteria5,6.By contrast,TLR2-
deficient mice show a normal inflammatory response
to LPS7,but macrophages from these animals are less
responsive to Gram-positive bacterial cell walls and
peptidoglycan7.These results are evidence ofTLR selec-
tivity in PAMP recognition,although other TLRs can
recognize the same components ofboth Gram-negative
and Gram-positive bacteria (see below).
response by phagocytic cells2.Peptidoglycan and lipotei-
choic acid from GRAM-POSITIVE BACTERIA are other PAMPs
that have the ability to activate the NUCLEAR FACTOR κB
(NFκB) signalling pathways and the production of
CYTOKINES. The secretion of cytokines by circulating
monocytes/neutrophils and tissue macrophages in
response to PAMPs requires a cascade of signalling
events,the details ofwhich have been clarified in recent
years.In particular,the involvement of TOLL-LIKE RECEPTORS
(TLRs) has received significant attention.
The Tollprotein was first discovered as an essential
molecule for the establishment ofthe dorsoventral axis in
the Drosophilaembryo.TLRsare mammalian homo-
logues ofthis protein,which are expressed at the surface
ofa specific group ofimmune cells known as the ANTIGEN-
PRESENTING CELLS(APCs).These cells are rapidly activated
by pathogens that bind to specific TLRs.Members ofthe
TLR family share characteristic extracellular and cyto-
plasmic domains3.Their extracellular domains include
Figure 1 |The family of TLRs and pro-inflammatory signal-transduction pathways that recruit NFκB. The extracellular domains of Toll-like receptors (TLRs)
include multiple leucine-rich repeats; TLR cytoplasmic domains are similar to the cytoplasmic portion of the interleukin 1 (IL-1) receptor (IL-1R). TLR2 recognizes the
pathogen-associated molecular patterns that are produced by Gram-positive (Gram+) bacterial cell wall components. TLR4, in association with CD14 and a molecule
known as MD-2, is crucial for the recognition of lipopolysaccharide (LPS) from Gram-negative (Gram–) bacteria. Flagellin, the principal element of bacterial flagella, is a
highly virulent molecule that is recognized by TLR5. TLR9 is required for the inflammatory response that is triggered by bacterial DNA. TLR3 engages the innate immune
response in the presence of viruses that produce double-stranded RNA (dsRNA). The broad spectrum of components recognized by these receptors indicates that
TLRs form heteromeric complexes. The cytoplasmic domain of TLR2 can form functional pairs with TLR6 and TLR1, leading to signal transduction and cytokine gene
expression. All TLRs activate signalling pathways that are similar to those activated by IL-1, because they share a Toll/IL-1R homology domain that can interact with the
adaptor protein MyD88. p50 and p65 are the two most common DNA-binding subunits of the nuclear factor κB (NFκB) dimer, and have the ability to trigger the
transcription of target genes that encode cytokines, chemokines, proteins of the complement system, enzymes, adhesion molecules, immune receptors and others. See
main text for details of the kinases involved in the NFκB nuclear translocation. ACP1, accessory protein 1; IKAP, IκB kinase complex (IKK-αβγ)-associated protein; IκB,
inhibitor of NFκB; IRAK, IL-1R-associated kinase; LTA, lipoteichoic acid; NIK, NFκB-inducing kinase; PGN, peptidoglycan; RIP, receptor-interacting protein; TNF, tumour
necrosis factor; TNFR, TNF receptor; TRADD, TNFR1-associated protein with death domain; TRAF, TNFR-associated factor; Ub, ubiquitin.
2 2 6 | MARCH 2002 | VOLUME 3
R E V I E W S
detrimental to the CNS,because it takes place rapidly in
response to systemic and cerebral insults.The endoge-
nous expression ofCD14 and numerous TLRs might
engage pro-inflammatory signal-transduction pathways
and the production ofcytokines by microglia.One ofthe
beneficial consequences ofsuch microglial reactivity is
the release ofneurotrophic factors and other molecules
that have important roles in brain homeostasis,neuro-
protection and repair in the case ofinjury.Once engaged
in severe infections,sustained microglial reactivity can
overproduce inflammatory molecules and alter the BBB,
a mechanism that seems to be central to several neurode-
generative disorders and demyelinating diseases. As
microglial cells are the APCs ofthe brain,they are proba-
bly crucial for cell-specific immunity against neuronal
elements.A better understanding ofthe innate immune
response in cerebral tissue could lead us to the funda-
mental mechanisms that underlie the capability ofthe
brain to mount an inflammatory response that either
protects against or contributes to neuronal damage.
humans.Accordingly,a single infection would be able to
trigger an innate immune response that can eventually
progress to a noxious adaptive immune response.
There is substantial evidence that molecules of the
innate immune reaction can be harmful to neurons and
oligodendrocytes,whereas other observations indicate
that inflammation is actually beneficial to recovery.The
cellular source ofthe cytokines that are involved and the
nature oftheir cognate receptors might help to explain
the discrepancies betweenstudies.The chronic produc-
tion ofinnate immune proteins and the presence ofcells
ofthe adaptive immune system in the cerebral environ-
ment could be essential features ofneurodegeneration.
However,this possibility has to be placed in a context of
causes or consequences that involve many players,
including genetic background,gender and environment.
The innate immune response that takes place in
the CNS during systemic infection is unlikely to be
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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.
The following terms in this article are linked online to:
CD14 | GABAAreceptor 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
ALS-parkinsonism/dementia complex of Guam | Alzheimer’s
disease | amyotrophic lateral sclerosis | frontotemporal dementia |
Huntington’s disease | multiple sclerosis | Parkinson’s disease |
Encyclopedia of Life Sciences: http://www.els.net/
antigen presentation to lymphocytes | blood–brain barrier |
microglia | nervous and immune system interactions |
Access to this interactive links box is free online.