Axon regeneration in the Central Nervous System (CNS) is extremely restricted after injury. This situation differs from that in the Peripheral Nervous System (PNS), where long-distance axon regeneration and functional recovery does happen. Dorsal root ganglion (DRG) neurons system is ideally suited to study the different properties, in terms of regeneration capability, of the PNS versus the CNS since they are sensory pseudo-unipolar neurons that have a bifurcate axon and extend one axonal branch into the PNS and another into the CNS. After peripheral, but not central, injury, different signals are triggered and transported to the cell body, conveying to reprogram the cell and activate its intrinsic regenerative capacity. In fact, peripheral injury-induced reprogramming allows certain extent of regeneration on the central branch, demonstrating the importance of overcoming the intrinsic blockage. This event is called conditioning lesion. Nerve injury causes inflammation, which is broadly characterised by a cascade of vascular and cellular events that culminate in the recruitment of immune cells to the damaged area attracted by chemoattrattans. Phagocytes such as polymorphonuclear neutrophilis, eosinophilis, monocytes and macrophages play a vital role in host defense against microbial phatogens and these immune cells express constitutively the plasma membrane NADPH oxidase (NOX). NOX's function is to produce Reactive Oxygen Species (ROS) to combat external phagocytated infectious particles. Here, we show that ROS, which are usually believed to promote axonal dieback and degeneration after injury, are required for axonal regeneration in the peripheral nerve and in the spinal cord (central nervous system), including after a conditioning lesion. In particular, CX3CR1-dependent recruitment of inflammatory cells is required for ROS induction in the injured sciatic nerve and dorsal root ganglion (DRG) cell bodies. Thanks to a crosstalk with the neuronal cell, inflammatory cells release NOX2 which is then incorporated in injured axons via endocytosis and is retrogradely transported, in its active form, in axonal endosomes towards the cell body via an importin ß1 and dynein dependent mechanism. Endosomal NOX2 oxidizes PTEN at cysteine residues, which leads to PTEN inactivation stimulating PI3K-pAkt signalling which plays a key role in cell proliferation and survival in response to growth factors, hormones, and cytokine stimulation.
Il crossttalk tra neurone e cellule immunitarie innesca un pathway ossidativo dipendente da NOX a favore della rigenerazione assonale la rigenerazione degli assoni nel Sistema Nervoso Centrale (SNC) è estremamente limitato dopo l'infortunio. Questa situazione è diversa da quella del sistema nervoso periferico (SNP), dove la rigenerazione degli assoni a lunga distanza e recupero funzionale accade. radici dorsali sistema gangliari (DRG) neuroni è ideale per studiare le diverse proprietà, in termini di capacità di rigenerazione, del PNS rispetto al sistema nervoso centrale dal momento che sono i neuroni pseudo-unipolare sensoriali che hanno un assone biforcuta e si estendono un ramo assonale nel PNS e un altro nel SNC. Dopo lesioni periferiche, ma non centrale, diversi segnali vengono attivati e trasportati al corpo cellulare, trasmettendo riprogrammare la cella e attivare la sua capacità rigenerativa intrinseca. Infatti, periferiche riprogrammazione lesioni indotte consente certa misura della rigenerazione sul ramo centrale, dimostrando l'importanza di superare il blocco intrinseca. Questo evento viene chiamato condizionata lesione. lesione del nervo provoca l'infiammazione, che è ampiamente caratterizzato da una cascata di eventi vascolari e cellulari che culminano nel reclutamento di cellule immunitarie per l'area danneggiata attratti dalla chemoattrattans. Fagociti come i neutrofili polimorfonucleati, eosinophilis, monociti e macrofagi svolgono un ruolo fondamentale nella difesa dell'ospite contro phatogens microbiche e queste cellule immunitarie esprimono costitutivamente la NADPH ossidasi membrana plasmatica (NOX). la funzione di NOX è quella di produrre specie reattive dell'ossigeno (ROS) per combattere le particelle infettive phagocytated esterno. Qui, dimostriamo che ROS, che di solito sono creduto per promuovere deperimento assonale e degenerazione dopo l'infortunio, sono necessarie per la rigenerazione assonale nel nervo periferico e nel midollo spinale (sistema nervoso centrale), anche dopo un condizionamento lesione. In particolare, è richiesto il reclutamento CX3CR1-dipendente delle cellule infiammatorie per l'induzione di ROS nei corpi cellulari feriti nervo sciatico e dorsale radice gangli (DRG). Grazie ad una diafonia con la cellula neuronale, cellule infiammatorie rilasciare NOX2 che viene poi integrato in assoni danneggiati tramite endocitosi e viene trasportato retrogradely, nella sua forma attiva, in endosomi assonale verso il corpo cellulare tramite un ß1 importina e dineina meccanismo dipendente. NOX2 endosomali ossida PTEN a residui di cisteina, che porta a PTEN inattivazione stimolare segnalazione PI3K-pAkt che svolge un ruolo chiave nella proliferazione cellulare e la sopravvivenza in risposta a fattori di crescita, ormoni, e la stimolazione di citochine.
"Neuronal immune crosstalk triggers axonal proregenerative NOX-dependent oxidative signaling"
TANTARDINI, ELENA
2014/2015
Abstract
Axon regeneration in the Central Nervous System (CNS) is extremely restricted after injury. This situation differs from that in the Peripheral Nervous System (PNS), where long-distance axon regeneration and functional recovery does happen. Dorsal root ganglion (DRG) neurons system is ideally suited to study the different properties, in terms of regeneration capability, of the PNS versus the CNS since they are sensory pseudo-unipolar neurons that have a bifurcate axon and extend one axonal branch into the PNS and another into the CNS. After peripheral, but not central, injury, different signals are triggered and transported to the cell body, conveying to reprogram the cell and activate its intrinsic regenerative capacity. In fact, peripheral injury-induced reprogramming allows certain extent of regeneration on the central branch, demonstrating the importance of overcoming the intrinsic blockage. This event is called conditioning lesion. Nerve injury causes inflammation, which is broadly characterised by a cascade of vascular and cellular events that culminate in the recruitment of immune cells to the damaged area attracted by chemoattrattans. Phagocytes such as polymorphonuclear neutrophilis, eosinophilis, monocytes and macrophages play a vital role in host defense against microbial phatogens and these immune cells express constitutively the plasma membrane NADPH oxidase (NOX). NOX's function is to produce Reactive Oxygen Species (ROS) to combat external phagocytated infectious particles. Here, we show that ROS, which are usually believed to promote axonal dieback and degeneration after injury, are required for axonal regeneration in the peripheral nerve and in the spinal cord (central nervous system), including after a conditioning lesion. In particular, CX3CR1-dependent recruitment of inflammatory cells is required for ROS induction in the injured sciatic nerve and dorsal root ganglion (DRG) cell bodies. Thanks to a crosstalk with the neuronal cell, inflammatory cells release NOX2 which is then incorporated in injured axons via endocytosis and is retrogradely transported, in its active form, in axonal endosomes towards the cell body via an importin ß1 and dynein dependent mechanism. Endosomal NOX2 oxidizes PTEN at cysteine residues, which leads to PTEN inactivation stimulating PI3K-pAkt signalling which plays a key role in cell proliferation and survival in response to growth factors, hormones, and cytokine stimulation.È consentito all'utente scaricare e condividere i documenti disponibili a testo pieno in UNITESI UNIPV nel rispetto della licenza Creative Commons del tipo CC BY NC ND.
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https://hdl.handle.net/20.500.14239/19792