Abstract
BackgroundAlthough 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.MethodsSeveral 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.ResultsMicroarray 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.ConclusionsThese 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 changes.
Highlights
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
Peripheral LPS challenge triggers an inflammatory response in the brain To induce systemic inflammation, mice were injected with a single high dose of LPS (100 μg i.p.); 6 hours following injection, plasma from all mice injected with LPS displayed significantly elevated levels of interleukin-1 β (IL-1β) and IL-6 (Figure 1A)
Levels of IL-1β returned to baseline between 6 and 12 hours following injection and IL-6 levels remained elevated until 48 hours
Summary
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. 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. By mechanisms that remain to be fully established, systemic infection or inflammation can have a profound effect on the central nervous system (CNS), manifesting in a number of behavioural adaptations, as well as fever and increased neuroendocrine activation. Malaise, anorexia, lethargy and, in severe cases, neuropsychiatric disorders, such as depression and anxiety [1]. Sickness behaviours occur during acute bacterial or viral infections, and during chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis [2,3,4]. The prolonged depression and anxiety that ensues represents a major burden to patients, not least because these detrimental comorbidities lead to a poorer clinical outcome
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