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Laboratory of Molecular Endocrinology, CHUL Research Center and Department of Anatomy and Physiology, Laval University, Québec, Canada G1V 4G2
1Correspondence: Laboratory of Molecular Endocrinology, CHUL Research Center and Department of Anatomy and Physiology, Laval University, 2705, boul. Laurier, Québec, Canada G1V 4G2. E-mail: Serge.Rivest{at}crchul.ulaval.ca
The recent characterization of human homologues of Toll
may be the missing link for the transduction events leading to NF-
B
activity and proinflammatory gene transcription during innate immune
response. Indeed, CD14 is not thought to participate directly in the
cell signaling, but rather one or more of the mammalian Toll-like
receptors (TLRs) acts in concert with the lipopolysaccharide (LPS)
receptor to discriminate between microbial pathogens or their products
and initiate transmembrane signaling. Mammalian cells may express as
many as 10 distinct TLRs, although the importance of TLR4 in response
to gram-negative bacteria and LPS is now supported by the fact that
TLR4-mutated mice are LPS resistant. We investigated the expression of
TLR4 across the rat brain under basal conditions and in response to
systemic LPS and IL-1ß injection. We first cloned the rat TLR4 cDNA
via RNA isolation and polymerase chain reaction (PCR) amplification
with a proofreading polymerase. Total RNA was isolated from the rat
liver tissue using Tri-Reagent and reverse transcribed into cDNA using
Superscript II reverse transcriptase and an oligonucleotide primer with
a degenerate 3' end of sequence 5'-T12(GAC)N-3'. Positive hybridization
signal was found in the leptomeninges, choroid plexus (chp),
subfornical organ, organum vasculosum of the lamina terminalis, median
eminence, and area postrema. Scattered small cells also displayed a
convincing hybridization signal within the brain parenchyma. Few
well-defined nuclei exhibited positive TLR4 transcript: the
supramamillary nucleus, cochlear nucleus, and the lateral reticular
nucleus. The circumventricular organs, the leptomeninges, and chp also
exhibited constitutive expression of the LPS receptor mCD14. In
contrast to the strong up-regulation of the gene encoding mCD14 during
endotoxemia, neither LPS nor IL-1ß caused a convincing increase in
the TLR4 mRNA levels across the CNS. A down-regulation of the gene
encoding TLR4 was found in the cerebral tissue of immune-challenged
animals. The constitutive expression of both mCD14 and TLR4 may explain
the innate immune response in the brain, which originates from the
structures devoid of blood–brain barrier in presence of circulating
LPS.—Laflamme, N., Rivest, S. Toll-like receptor 4: the missing link
of the cerebral innate immune response triggered by circulating
gram-negative bacterial cell wall components.
Key Words: circumventricular organs • innate immune response • in situ hybridization histochemistry • inflammation • lipopolysaccharide • proinflammatory cytokines • microglia • macrophages • NF-B • septic shock
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