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Perpheral autoimmunity induces central neuro-inflammation and hippocampal neurogenesis impairment in a murine model of collagen induced Rheumatoid Arthritis

Sutthiwarotamakun, Rungrut (2011) Perpheral autoimmunity induces central neuro-inflammation and hippocampal neurogenesis impairment in a murine model of collagen induced Rheumatoid Arthritis. PhD thesis, University of Glasgow.

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Abstract

Background: Psychiatric disorders are common in patients with autoimmune diseases such as rheumatoid arthritis. These disorders are poorly understood and are an important co-morbidity. They may occur as a consequence of the effects of the autoimmune inflammation on the central nervous system. Peripheral inflammation inducing central cytokine production in the CNS has been documented in acute inflammatory models such as after systemic LPS challenge, and cytokine administration has been shown to induce cognitive impairment and mood disorders. These disorders may be due to the central action of cytokines on neurogenesis and reduced hippocampal neurogenesis has been implicated in depression and cognitive decline. Peripheral inflammation and some specific cytokines have been reported to inhibit hippocampal neurogenesis, resulting in cognition impairment and depressive-like behaviour in animal models. Hypothesis: Based on this evidence, we hypothesized that peripheral inflammation associated with arthritis can induce central production of inflammatory mediators in the brain contributing to reduction in hippocampal neurogenesis thereby offering a mechanism and potential therapeutic targets for RA-associated psychiatric disorders. Aims and Methods: The aim of this project is 1) to investigate whether peripheral immune/inflammatory responses during arthritis can induce changes in inflammatory mediators in brains of collagen induced arthritis (CIA) mice, using this as a model for an adaptive immune response contributing to neurological disease development similar to the human disease. We used Luminex bead-based screening assays to determine a wide range of inflammatory mediator proteins in single small volume samples obtained from mouse brain tissues. In the same tissues, the transcription levels of genes encoding these inflammatory mediators were also quantified using real-time PCR and quantified as absolute copy numbers. 2) To investigate whether peripheral immune/inflammatory responses during arthritis can induce changes in hippocampal neurogenesis in brains of collagen induced arthritis (CIA) mice, we also measure changes in hippocampal neurogenesis in CII immunized mice using the immunohistochemistry of neuronal marker doublecortin (DCX). In order to confirm that changes in both inflammatory mediators and hippocampal 3 neurogenesis were due to peripheral inflammation, CII immunized mice were given peripheral anti TNF-α etanercept treatment. Inflammatory mediator profiles and hippocampal neurogenesis in brains of etanercept-treated CII immunized mice were compared to PBS -treated CII immunized mice and naive control mice. Results: Systemic etanercept treatment attenuated arthritis in CII immunized mice. IL-1β, IL-5, CXCL1 and FGF2 protein were increased in the serum of CII immunized mice. In addition, we found up-regulation of protein and gene concentrations of IL-1β, IL-1-α, TNF-α, IL-6, IFN-γ, IL-2, IL-12, IL-4, IL-5, CXCL1, CXCL0 and CCL2, VEGF and FGF2 in brains of CII immunized mice compared to those in naive control mice. The reduction in number of DCXpositive neurons in the dentate gurus of CII immunized mice compared to those in naive control mice, suggesting the impairment in hippocampus neurogenesis in CII immunized mice. In addition, reduction of inflammatory mediators, including IL-1β, TNF-α, IL-12, CXCL1, and increases of IL-6, IL-2 and VEGF and FGF2 protein concentrations were observed in brains of etanercept-treated CII immunized mice compared to those in untreated CII immunized mice. In addition, the impairment in hippocampal neurogenesis was reversed by peripheral etanercept treatment in CII immunized mice. In conclusion, the data of this thesis shows that peripheral inflammation during arthritis potentially induces production of inflammatory mediators in brains of CII immunized mice. Up-regulation of these inflammatory mediators in the brain may be associated with the impairment in hippocampal neurogenesis of CII immunized mice. In addition, peripheral etanercept treatment seems to have protective effect against peripheral-induced brain inflammation and the impairment in hippocampal neurogenesis in CII immunized mice. In summary, we demonstrated that peripheral inflammation resulting from arthritis may induce brain inflammation and contribute to the impairment of hippocampal neurogenesis. Systemic etanercept treatment not only attenuated joint inflammation, but also reduced brain inflammation and reversed the impairment in hippocampal neurogenesis resulting from peripheral inflammation in CII immunized mice.

Item Type: Thesis (PhD)
Qualification Level: Postdoctoral
Keywords: Rheumatoid Arthritis, depression, hippocampal neurogenesis, autoimmunity, peripheral inflammation, neuroinflammation
Subjects: R Medicine > R Medicine (General)
R Medicine > RS Pharmacy and materia medica
Q Science > Q Science (General)
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Supervisor's Name: McInnes, Prof. Iain
Date of Award: 2011
Depositing User: Miss Rungrut Sutthiwarotamakun
Unique ID: glathesis:2011-3027
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 28 Nov 2011
Last Modified: 10 Dec 2012 14:03
URI: http://theses.gla.ac.uk/id/eprint/3027

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