Impact of peripheral inflammation in the brain : new roles for the anti-inflammatory molecule Annexin A1

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

Pathological Angiogenesis Requires Syndecan-4 for Efficient VEGFA-Induced VE-Cadherin Internalization

Objective: VEGFA (Vascular endothelial growth factor A) and its receptor VEGFR2 (vascular endothelial growth factor receptor 2) drive angiogenesis in several pathologies, including diabetic retinopathy, wet age-related macular degeneration, and cancer. Studies suggest roles for HSPGs (heparan sulfate proteoglycans) in this process, although the nature of this involvement remains elusive. Here, we set to establish the role of the HSPG SDC4 (syndecan-4) in pathological angiogenesis. Approach and Results: We report that angiogenesis is impaired in mice null for SDC4 in models of neovascular eye disease and tumor development. Our work demonstrates that SDC4 is the only SDC whose gene expression is upregulated during pathological angiogenesis and is selectively enriched on immature vessels in retinas from diabetic retinopathy patients. Combining in vivo and tissue culture models, we identified SDC4 as a downstream mediator of functional angiogenic responses to VEGFA. We found that SDC4 resides at endothelial cell junctions, interacts with vascular endothelial cadherin, and is required for its internalization in response to VEGFA. Finally, we show that pathological angiogenic responses are inhibited in a model of wet age-related macular degeneration by targeting SDC4. Conclusions: We show that SDC4 is a downstream mediator of VEGFA-induced vascular endothelial cadherin internalization during pathological angiogenesis and a potential target for antiangiogenic therapies.acceptedVersionPeer reviewe

Myeloid-Derived Vascular Endothelial Growth Factor and Hypoxia-Inducible Factor Are Dispensable for Ocular Neovascularization—Brief Report

OBJECTIVE: Ocular neovascularization (ONV) is a pathological feature of sight-threatening human diseases, such as diabetic retinopathy and age-related macular degeneration. Macrophage depletion in mouse models of ONV reduces the formation of pathological blood vessels, and myeloid cells are widely considered an important source of the vascular endothelial growth factor A (VEGF). However, the importance of VEGF or its upstream regulators hypoxia-inducible factor-1α (HIF1α) and hypoxia-inducible factor-2α (HIF2α) as myeloid-derived regulators of ONV remains to be determined. APPROACH AND RESULTS: We used 2 mouse models of ONV, choroidal neovascularization and oxygen-induced retinopathy, to show that Vegfa is highly expressed by several cell types, but not myeloid cells during ONV. Moreover, myeloid-specific VEGF ablation did not reduce total ocular VEGF during choroidal neovascularization or oxygen-induced retinopathy. In agreement, the conditional inactivation of Vegfa, Hif1a, or Epas1 in recruited and resident myeloid cells that accumulated at sites of neovascularization did not significantly reduce choroidal neovascularization or oxygen-induced retinopathy. CONCLUSIONS: The finding that myeloid cells are not a significant local source of VEGF in these rodent models of ONV suggests that myeloid function in neovascular eye disease differs from skin wound healing and other neovascular pathologies

Figurazioni sociali e trasfigurazioni testuali: il potere della scrittura-lettura sulla rifigurazione delle identità

La scrittura e la lettura influenzano e significano l'identità delle culture, in quanto le trasfigurazioni testuali, poetiche e, in particolare, narrative, arricchiscono le figurazioni sociali e co-modellano l'io analogo, metaforico, co-presente nell'ipseità del soggetto, la cui identità viene suggerita dalla personografia narrativa. Nel contributo vengono messi in relazione critica C. Lévi-Strauss, H.R. Jauss, N. Holland Norman, R. Girard e G. Flaubert

Che cos’è un’esposizione universale? È il mondo che si incontra. Un racconto sulle origini del pubblico di massa

Un racconto sulla nascita del pubblico di massa in occasione delle grandi esposizioni universali del XIX secolo. Una storia culturale della modernità industriale ricostruita attraverso le pagine e le testimonianze letterari dei grandi protagonisti di quella stagione della cultura occidentale

EXPO 1851-2015. Storie e immagini delle grandi esposizioni

EXPO 1851-2015. Storie e immagini delle Grandi Esposizioni è un volume dedicato alla storia delle Esposizioni universali dalla loro nascita ad oggi, diretto dal professor Alberto Abruzzese, sociologo della comunicazione, già docente all’università IULM di Milano. Il volume è curato dal professor Luca Massidda, docente di Sociologia Urbana presso la Scuola di Architettura e Design di Ascoli Piceno, Università di Camerino. L’opera è strutturata in tre sezioni. La prima, dal titolo Storie, analizza l’importanza delle Grandi Esposizioni - da Londra 1851 a Shanghai 2010 - secondo diverse ottiche tematiche (dal lavoro alla scienza, alla tecnologia, all’arte, all’impatto architettonico, alla comunicazione). La seconda sezione, Geografie: le Grandi Esposizioni nel mondo e in Italia ripercorre la storia delle esposizioni secondo un criterio geografico – Europa, Americhe e Asia - dando particolare risalto all’Italia con le Esposizioni di Milano 1906, Torino 1911 e Roma 1942 (mai attuata a causa della guerra). La terza sezione del volume, dal titolo Primo piano: Milano 2015, è dedicata all’Expo attuale, mettendone in luce la genesi, le problematiche progettuali, architettoniche ed espositive, l’importanza economica per Milano e per il sistema-Paese e il significato del tema “Nutrire il Pianeta, energia per la Vita” che costituisce l’asse culturale portante della manifestazione. Il volume raccoglie 42 saggi, tutti firmati da studiosi che si sono già autorevolmente occupati del tema delle Grandi Esposizioni universali. Chiudono infine il volume alcune interviste a personaggi delle istituzioni della cultura sul significato di Expo 2015 e il testo integrale della “Carta di Milano”