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

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.

Influenza infection triggers disease in a genetic model of experimental autoimmune encephalomyelitis

“…Nevertheless, the data presented here add to the understanding of how systemic inflammation affects the CNS by demonstrating that peripheral infection with a live virus induces the up-regulation of IFN-responsive genes in the cerebellum and spinal cord. These data strongly agree with those from Thomson et al, which clearly show an effect of systemic TLR7 ligation and IFN gene induction in the brain (36). Notably, influenza viral RNA is recognized by TLR7 (47).…”

Inflammatory memory sensitizes skin epithelial stem cells to tissue damage

“…To determine whether this heightened sensitivity might be triggered by other inflammatory stimuli, we replaced IMQ with topical treatments of vitamin D analog MC903 (to model atopic dermatitis) 9 , 12-O-tetradecanoylphorbol 13-acetate (TPA) 10 (inflammation-induced hyperplasia), epidermal abrasion wounding (“sterile” wound) 11 , or infection with fungal pathogen Candida albicans 12 . In all cases, wounds healed faster in inflammation-experienced skin (Fig.…”

Persistent systemic inflammation and symptoms of depression among patients with COPD in the ECLIPSE cohort

“…For example, previous studies showed a relationship between inflammatory biomarkers and symptoms of depression in patients with type 2 diabetes or heart failure [9,10]. In addition, a recent study in mice showed that peripheral inflammation is associated with remote global gene expression changes in the brain and this may explain how inflammation may contribute to the development of symptoms of depression in patients with chronic diseases [11].…”