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Title: Impact of peripheral inflammation in the brain : new roles for the anti-inflammatory molecule Annexin A1
Author: Cristante, Enrico
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Growing evidence has shown that peripheral inflammation can trigger a central nervous system response, sometimes worsening pre-existing neurological conditions, breaking down the concept of brain as an immune-privileged organ. Understanding which components contribute to periphery-to-brain communication may help identify molecules exploitable for therapeutic intervention. Usually, inflammation is followed by resolution: one of the main effectors in this process during peripheral inflammation is Annexin A1, while its implications in the CNS are still unclear. This thesis provides evidence for a new face for the molecule: we observed a well-defined expression at blood brain barrier (BBB) at endothelial level and we detected, in vivo, significantly higher BBB permeability in the AnxA1 null mice due to disrupted inter-endothelial cell tight junctions, essentially as a consequence to changes in the actin cytoskeleton. Such changes are reminiscent of early MS pathology, a relationship confirmed by detecting a selective loss of ANXA1 in the plasma and cerebrovascular endothelium of MS patients. Under peripheral inflammatory conditions (i.p. lipopolysaccharide, LPS), in vivo data suggested an inherent sex difference in BBB response, while in vitro studies confirmed the protective action of sex hormone 17β-Estradiol on the endothelium through ANXA1 modulation. Within the CNS, we detected a constitutively higher microglial density and pro-inflammatory environment in the Anxa1 null mouse, which worsened upon peripheral inflammation. In a neurodegeneration model (6-hydroxydopamine), genotype-related differences in microglial invasion occurred, while subsequent peripheral inflammatory challenges synergised and caused worse dopaminergic neuronal loss only in the knock-out model. These original data unveil a novel functional paradigm for ANXA1 as a “translator” between peripheral immune system and CNS through novel pathways compared to its well-characterized peripheral role. In addition, this study opens up a novel path to find therapeutic applications against disorders characterized by central and peripheral inflammation.
Supervisor: Solito, Egle ; Gillies, Glenda Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available