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.