Peripheral inflammation remotely triggers global gene expression changes in the brain

Thomson, Carolyn (2014) Peripheral inflammation remotely triggers global gene expression changes in the brain. PhD thesis, University of Glasgow.

Abstract

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 peripheral immune activation has on neural circuitry remains unclear. Therefore, the primary aim of this thesis was to develop a better understanding of the bidirectional relationship, and communication pathways, that exist between the immune system and the nervous system.
By utilising transcriptomics in a well-characterised murine model of systemic inflammation, I have investigated the molecular mechanisms by which inflammation originating in the periphery can induce transcriptional modulation in the brain. Systemic inflammation was induced in male C57BL/6 mice via intraperitoneal injection of lipopolysaccharide (LPS). After 48 hours, whole brain transcriptional profiles were assessed, and compared to that of a vehicle- treated control group, 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 the brains of mice, following the induction of different sterile, and TLR- dependent, models of peripheral inflammation.
Microarray analysis of whole brains collected 48hr after LPS challenge revealed increased transcription of a range of interferon-stimulated genes (ISGs) in the brain, including a significant upregulation of the classic interferon-induced chemokine CXCL10. This transcriptional profile could not be reproduced by the systemic administration of TNFα, or following lipoteichoic acid-induced systemic inflammation. However, target genes remained induced in the brain following daily LPS injections, in the absence of a detectable inflammatory cytokine response in the periphery.
1
The central induction of CXCL10 suggests that acute exposure to LPS in the periphery may prime the brain for T cell infiltration. This prompted an investigation into whether leukocytes infiltrated the brain following daily systemic LPS injections. First, the inflammatory chemokine repertoire in the brains of LPS treated mice was systematically characterised. In addition to Cxcl10, repeated injection of LPS in the periphery triggered a transient increase in the transcription of a number of other inflammatory chemokines in the brain. Chemokine induction was associated with an influx of leukocytes from the periphery, and an increase in mRNA encoding the relevant chemokine receptors. Therefore, chemokine induction in the brain following daily systemic LPS injections may mediate the recruitment of leukocytes from the periphery.
The transcriptional response in the brain following systemic LPS challenge is indicative of a peripherally triggered inflammatory response in the brain. The data described in this thesis highlight a potential mechanism of gene modulation in the brain which may be dependent on a TLR-induced type I interferon response. Considerable evidence links type I interferons to psychiatric disorders, and consequently, interferon production in the brain could represent an important mechanism linking peripheral TLR-induced inflammation with behavioural changes. In addition, the data described in this thesis demonstrate that chronic exposure to LPS in the periphery may remotely modulate the recruitment of leukocytes to the brain. This highlights a potential protective mechanism that could prevent a chronic bacterial infection from spreading from the periphery to the brain.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Innate immunity, central nervous system, toll-like receptors, chemokines, interferons, microarray, brain
• Subjects: Q Science > QR Microbiology > QR180 Immunology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Immunology & Infection
• Supervisor's Name: Jonathan, Prof Cavanagh and Gerard, Prof Graham
• Date of Award: 2014
• Depositing User: Miss Carolyn Thomson
• Unique ID: glathesis:2014-5390
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 31 Jul 2014 08:48
• Last Modified: 31 Jul 2014 08:57
• URI: https://theses.gla.ac.uk/id/eprint/5390