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Systemic inflammation and its impact on the brain
[Thesis]. Manchester, UK: The University of Manchester; 2012.
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Abstract
Stroke is a leading cause of death in the UK however there is only one currenttreatment, intravenous thrombolysis via administration of tissue plasminogen activator (tPA).The paucity of available treatments is not simply due to a lack of research as there have beenmany successful preclinical studies that have failed to translate to success in the clinic. TheStroke Therapy Academic Industry Roundtable (STAIR) have published several articles thatoutline a number of possible reasons for this lack of translation between pre-clinical andclinical research. One major reason highlighted is the failure to consider clinically relevantco-morbidities in preclinical studies.Therefore the key objectives of this thesis were to; (1) determine whether centralnervous system (CNS) changes occur in both animal models and patients with risk factors forstroke, (2) determine how neuroinflammatory changes induced in response to peripheralatherosclerosis are affected by the deletion of IL-1 signalling (3) establish whether aperipheral infection in atherosclerotic mice induces any cerebral ischaemic events and todetermine the inflammatory response in both the periphery and the brain.Neuroinflammation was assessed in patients at risk of stroke, the co-morbid JCR-LArat and the atherosclerotic ApoE-/- mouse. PET imaging revealed microglial activation in thebrain of JCR-LA (corpulent) rats and patients at risk of stroke. Microglial activation, vascularactivation, leukocyte infiltration and focal lipid deposition were observed in the brains ofatherosclerotic ApoE-/- mice. These findings show brain inflammation occurs in animals, andtentatively in humans, harbouring risk factors for stroke.Neuroinflammation was assessed in ApoE-/- mice crossed with IL-1 type 1 receptordeficient mice (ApoE-/-/IL-1R1-/-) and both neuroinflammation and systemic atherosclerosiswas assessed in ApoE-/- mice treated with an anti-IL-1β antibody. ApoE-/- mice fed Paigen orWestern diet develop vascular inflammation, microglial activation and leukocyte recruitmentin the brain, which are absent in ApoE-/-/IL-1R1-/-. Systemic neutralisation of IL-1β with ananti-IL-1β antibody reversed aortic plaque formation and reduced inflammatory cytokineexpression in peripheral organs. In the brain, vascular inflammation and leukocyte infiltrationinto the choroid plexus were reversed by IL-1β blockade in animals fed a Paigen diet. Theseresults indicate that IL-1 is a key driver of systemically-mediated cerebrovascularinflammation and that interventions against IL-1β could be therapeutically useful inatherosclerosis, dementia or stroke.ApoE-/- and C57BLJ/6 mice infected with Streptococcus (S.) pneumoniae wereassessed for spontaneous stroke events, neuroinflammation and systemic inflammatoryresponses to infection. Infection with S. pneumoniae in atherosclerotic mice did not inducespontaneous stroke. Raised levels of vascular activation were observed in all mice and analteration in leukocyte accumulation in infected atherosclerotic ApoE-/- mice. T cell, B celland granulocyte responses to both diet and infection were found to differ between ApoE-/-mice and control, C57BLJ/6, mice. Levels of the proinflammatory cytokines IL-1, IL-6 andIL-17 were also increased in response to S. pneumoniae infection in plasma, spleen and liver.These data indicate that atherosclerosis and S. pneumoniae infections not only have systemicinflammatory mechanisms but also effects that extend to the brain.Overall these findings demonstrate that risk factors for stroke cause alterations ininflammation in the brain. Therefore modelling of these risk factors is essential in futurepreclinical stroke research if new treatments for stroke are to be identified.