Peripheral inflammation is associated with remote global gene expression changes in the brain.


Although the central nervous system (CNS) was
once considered an immunologically privileged site, in recent years it
has become increasingly evident that cross talk between the immune
system and the CNS does occur. As a result, patients with chronic
inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel
disease or psoriasis, are often further burdened with neuropsychiatric
symptoms, such as depression, anxiety and fatigue. Despite the recent
advances in our understanding of neuroimmune communication pathways, the
precise effect of peripheral immune activation on neural circuitry
remains unclear. Utilizing transcriptomics in a well-characterized
murine model of systemic inflammation, we have started to investigate
the molecular mechanisms by which inflammation originating in the
periphery can induce transcriptional modulation in the brain.


different systemic and tissue-specific models of peripheral
toll-like-receptor-(TLR)-driven (lipopolysaccharide (LPS), lipoteichoic
acid and Imiquimod) and sterile (tumour necrosis factor (TNF) and
12-O-tetradecanoylphorbol-13-acetate (TPA)) inflammation were induced in
C57BL/6 mice. Whole brain transcriptional profiles were assessed and
compared 48 hours after intraperitoneal injection of lipopolysaccharide
or vehicle, using Affymetrix GeneChip microarrays. Target gene
induction, identified by microarray analysis, was validated
independently using qPCR. Expression of the same panel of target genes
was then investigated in a number of sterile and other TLR-dependent
models of peripheral inflammation.


analysis of whole brains collected 48 hr after LPS challenge revealed
increased transcription of a range of interferon-stimulated genes (ISGs)
in the brain. In addition to acute LPS challenge, ISGs were induced in
the brain following both chronic LPS-induced systemic inflammation and
Imiquimod-induced skin inflammation. Unique to the brain, this
transcriptional response is indicative of peripherally triggered,
interferon-mediated CNS inflammation. Similar models of sterile
inflammation and lipoteichoic-acid-induced systemic inflammation did not
share the capacity to trigger ISG induction in the brain.


data highlight ISG induction in the brain as being a consequence of a
TLR-induced type I interferon response. As considerable evidence links
type I interferons to psychiatric disorders, we hypothesize that
interferon production in the brain could represent an important
mechanism, linking peripheral TLR-induced inflammation with behavioural

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