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I forced displacement di popolazioni rappresentano un fenomeno ancestrale, che il diritto internazionale sta gradualmente affrontando e integrando, in particolare per fornire una risposta normativa alla protezione delle persone sfollate di forza. Tralasciando questo aspetto, ormai ben sviluppato nel diritto internazionale, che riguarda in particolare gli obblighi degli Stati riceventi, il presente lavoro di ricerca esplora le norme che si rivolgono direttamente o indirettamente agli Stati di origine delle migrazioni involontarie, al fine di anticiparle e prevenirle. Attraverso uno studio trasversale di diverse materie del diritto internazionale, ma anche attraverso l'analisi di alcuni concetti extra-giuridici che oggi tendono a influenzare l'evoluzione degli strumenti giuridici, questo studio parte da una duplice domanda: in primo luogo, scoprire se esistono norme specifiche riguardanti i fenomeni di forced displacement di popolazione, in particolare in termini di prevenzione e repressione; in secondo luogo, se sono stati formulati alcuni obblighi su questo punto in capo agli Stati di origine dei movimenti di popolazione. Queste domande nascono dall'osservazione concreta delle migrazioni forzate, e in particolare degli eventi che ne sono alla fonte, spesso rappresentati dalle azioni intraprese dagli stessi Stati, come nel caso dei contesti di violazione dei diritti umani e di conflitti armati. In effetti, questi movimenti migratori involontari si materializzano in contesti diversi, che richiedono quindi la mobilitazione di norme di diversa natura. La prima parte della tesi è stata dedicata alla ricerca di norme di prevenzione nel campo degli spostamenti forzati di popolazione, attraverso l'analisi delle diverse materie del diritto internazionale. La prima osservazione è che le norme pertinenti del diritto internazionale sono molto frammentate. Ciò implica che il corpus giuridico esistente, o in via di sviluppo, non considera gli spostamenti forzati come fenomeno, Forced population displacement is an age-old phenomenon that international law is gradually addressing, in particular in order to provide a normative response to the protection of forcibly displaced persons. Leaving aside this aspect, which is now well developed in international law, and which concerns in particular the obligations of receiving States, this research work explores the rules that are directly or indirectly addressed to the States of origin of involuntary migration, in order to anticipate and prevent it. Through a transversal study of several branches of international law, but also through the analysis of certain extra-legal concepts that now tend to influence the evolution of legal instruments, this study answers a double question: to discover if there are specific norms regarding the phenomena of forced population displacement, notably in terms of prevention and repression, and if certain obligations have been formulated on this point for the States of origin of population movements. These questions derive from the actual observation of forced migration, and in particular its sources, often represented by the actions undertaken by the States themselves, as is the case in contexts of human rights violations and armed conflicts. Indeed, forced population displacements materialise in multiple contexts, which therefore call for the mobilisation of rules of different nature. The first part of the thesis was dedicated to the search for prevention norms in the field of forced population displacement, through the analysis of the different branches of international law. The first observation is that the relevant rules of international law are very fragmented. This implies that the existing or developing body of law does not consider forced movements per se, but always in relation to the context in which they occur, as a consequence of the activity in question. For this purpose, the norms relating to the environment and climate change, but also to armed confli

Multiple sclerosis (MS) is characterized by macrophage accumulation and inflammatory infiltrates into the CNS contributing to demyelination. Because purinergic P2X7 receptor (P2X7R) is known to be abundantly expressed on cells of the hematopoietic lineage and of the nervous system, we further investigated its phenotypic expression in MS and experimental autoimmune encephalomyelitis conditions. By quantitative reverse transcription polymerase chain reaction and flow cytometry, we analyzed the P2X7R expression in human mononuclear cells of peripheral blood from stable and acute relapsing-remitting MS phases. Human monocytes were also challenged in vitro with pro-inflammatory stimuli such as the lipopolysaccharide, or the P2X7R preferential agonist 2'(3')-O-(4 Benzoylbenzoyl)adenosine 5'-triphosphate, before evaluating P2X7R protein expression. Finally, by immunohistochemistry and immunofluorescence confocal analysis, we investigated the P2X7R expression in frontal cortex from secondary progressive MS cases. We demonstrated that P2X7R is present and inhibited on peripheral monocytes isolated from MS donors during the acute phase of the disease, moreover it is down-regulated in human monocytes after pro-inflammatory stimulation in vitro. P2X7R is instead up-regulated on astrocytes in the parenchyma of frontal cortex from secondary progressive MS patients, concomitantly with monocyte chemoattractant protein-1 chemokine, while totally absent from microglia/macrophages or oligodendrocytes, despite the occurrence of inflammatory conditions. Our results suggest that inhibition of P2X7R on monocytes and up-regulation in astrocytes might contribute to sustain inflammatory mechanisms in MS. By acquiring further knowledge about P2X7R dynamics and identifying P2X7R as a potential marker for the disease, we expect to gain insights into the molecular pathways of MS.

Inflammation and oxidative stress are thought to play determinant roles in the pathogenesis of amyotrophic lateral sclerosis (ALS). Degenerating motor neurons produce signals that activate microglia to release reactive oxygen species (ROS) and proinflammatory cytokines, resulting in a vicious cycle of neurodegeneration. The ALS-causing mutant protein Cu+/Zn+ superoxide dismutase SOD1- G93A directly enhances the activity of the main ROS-producing enzyme in microglia, NADPH oxidase 2 (NOX2), a well-known player in the pathogenesis of ALS. Considering that extracellular ATP through P2X7 receptor constitutes a neuron-to-microglia alarm signal implicated in ALS pathology, we used primary microglial cells derived from transgenic SOD1-G93A mice and SOD1-G93A mice lacking the P2X7 receptor to investigate the effects of both pharmacological induction and genetic ablation of receptor activity on the NOX2 pathway. We observed that, in SOD1-G93A microglia, the stimulation of P2X7 receptor by 29-39- O-(benzoyl-benzoyl) ATP enhanced NOX2 activity in terms of translocation of p67phox to the membrane and ROS production; this effect was totally dependent on Rac1.We also found that, following P2X7 receptor stimulation, the phosphorylation of ERK1/2 was augmented in ALS microglia, and there was a mutual dependency between the NOX2 and ERK1/2 pathways. All of these microglia-mediated damaging mechanisms were prevented by knocking out P2X7 receptor and by the use of specific antagonists. These findings suggest a noxious mechanism by which P2X7 receptor leads to enhanced oxidative stress in ALS microglia and identify the P2X7 receptor as a promising target for the development of therapeutic strategies to slow down the progression of ALS.