The brain response to peripheral inflammation

Communication between the immune system and the central nervous system (CNS) is becoming increasingly topical as evidence suggests the two systems are intricately linked. Although the brain is considered an ‘immune-specialised’ tissue, it is not free from the influences of the periphery. Recent data indicate that peripheral immune stimulation can significantly affect the CNS, and patients with chronic inflammatory diseases, including rheumatoid arthritis (RA) and psoriasis, are often further burdened by the onset of neuropsychiatric conditions such as major depressive disorder (MDD), schizophrenia and anxiety. However, despite increases in our understanding, the precise mechanisms underpinning this relationship remain unclear. Therefore, the aim of this thesis is to investigate the communication pathways that exist between the immune system and the nervous system and to enhance our understanding of this bidirectional relationship. Using a well-characterised animal model of psoriasis-like skin inflammation, I have investigated the effects of cutaneous, peripheral inflammation on the brain. Psoriasis-like skin inflammation was induced in female C57BL/6 mice via the repeated application of Aldara cream to the shaved dorsal skin. Twenty-four hours after the fifth application, the transcriptional response in the brain was assessed and compared with mice treated with an aqueous control cream, using Affymetrix GeneChip arrays. The induction of target genes, identified using microarray analysis, was confirmed in an independent model using QPCR and was compared to the gene induction following a number of other inflammatory models, including a sterile model of cutaneous inflammation. Transcriptional profiling techniques allowed me to identify a number of differentially expressed genes in the brains of Aldara- and Imiquimod (IMQ)- treated mice when compared with the brains of control mice. This response included a range of interferon-stimulated genes (ISGs) and chemokines that were not induced in the peripheral blood leukocytes (PBL), and occurred independently of an overt cytokine response in the PBL. The brain ISG and chemokine response was not detected following a sterile model of cutaneous inflammation or following the intraperitoneal administration of Imiquimod.  The central induction of a number of chemokines prompted the evaluation of immune cell infiltration into the brain parenchyma. In addition, the functional consequences of topical Aldara treatment, and the involvement of inflammatory chemokines, were determined by assessing dentate neurogenesis and burrowing behaviour in wild-type and ACKR2-deficient mice. The transcriptional response following cutaneous IMQ-induced inflammation is indicative of a peripherally triggered inflammatory response in the brain. In addition, the data described in this thesis demonstrate a functional consequence of peripheral immune stimulation and suggest that cutaneous inflammation could modulate the recruitment of leukocytes to the brain. These data highlight a potential mechanism of TLR-dependent communication between the periphery and the brain that could be mediated through the activation of the afferent vagus nerve