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Overcoming the restricted axonal regenerative ability that limits functional repair following a central nervous system injury remains a challenge. Here we report a regenerative paradigm that we call enriched conditioning, which combines environmental enrichment (EE) followed by a conditioning sciatic nerve axotomy that precedes a spinal cord injury (SCI). Enriched conditioning significantly increases the regenerative ability of dorsal root ganglia (DRG) sensory neurons compared to EE or a conditioning injury alone, propelling axon growth well beyond the spinal injury site. Mechanistically, we established that enriched conditioning relies on the unique neuronal intrinsic signaling axis PKC-STAT3-NADPH oxidase 2 (NOX2), enhancing redox signaling as shown by redox proteomics in DRG. Finally, NOX2 conditional deletion or overexpression respectively blocked or phenocopied enriched conditioning-dependent axon regeneration after SCI leading to improved functional recovery. These studies provide a paradigm that drives the regenerative ability of sensory neurons offering a potential redox-dependent regenerative model for mechanistic and therapeutic discoveries.

COVID-19 is an infectious disease caused by the coronavirus SARS-CoV-2, which was first reported in Wuhan, China, in December 2019 and has caused a global pandemic. Acute respiratory distress syndrome (ARDS) is a common feature of severe forms of COVID-19 and can lead to respiratory failure, especially in older individuals. The increasing recognition of the neurotropic potential of SARS-CoV-2 has sparked interest in the role of the nervous system in respiratory failure in people with COVID-19. However, the neuroimmune interactions in the lung in the context of ARDS are poorly understood. In this Perspectives article, we propose the concept of the neuroimmune unit as a critical determinant of lung function in the context of COVID-19, inflammatory conditions and ageing, focusing particularly on the involvement of the vagus nerve. We discuss approaches such as neurostimulation and pharmacological neuromodulation to reduce tissue inflammation with the aim of preventing respiratory failure.

Over the past decade, we have witnessed a flourishing of novel strategies to enhance neuroplasticity and promote axon regeneration following spinal cord injury, and results from preclinical studies suggest that some of these strategies have the potential for clinical translation. Spinal cord injury leads to the disruption of neural circuitry and connectivity, resulting in permanent neurological disability. Recovery of function relies on augmenting neuroplasticity to potentiate sprouting and regeneration of spared and injured axons, to increase the strength of residual connections and to promote the formation of new connections and circuits. Neuroplasticity can be fostered by exploiting four main biological properties: neuronal intrinsic signalling, the neuronal extrinsic environment, the capacity to reconnect the severed spinal cord via neural stem cell grafts, and modulation of neuronal activity. In this Review, we discuss experimental evidence from rodents, nonhuman primates and patients regarding interventions that target each of these four properties. We then highlight the strengths and challenges of individual and combinatorial approaches with respect to clinical translation. We conclude by considering future developments and providing views on how to bridge the gap between preclinical studies and clinical translation.

Axonal regenerative failure is a major cause of neurological impairment following central nervous system (CNS) but not peripheral nervous system (PNS) injury. Notably, PNS injury triggers a coordinated regenerative gene expression programme. However, the molecular link between retrograde signalling and the regulation of this gene expression programme that leads to the differential regenerative capacity remains elusive. Here we show through systematic epigenetic studies that the histone acetyltransferase p300/CBP-associated factor (PCAF) promotes acetylation of histone 3 Lys 9 at the promoters of established key regeneration-associated genes following a peripheral but not a central axonal injury. Furthermore, we find that extracellular signal-regulated kinase (ERK)-mediated retrograde signalling is required for PCAF-dependent regenerative gene reprogramming. Finally, PCAF is necessary for conditioning-dependent axonal regeneration and also singularly promotes regeneration after spinal cord injury. Thus, we find a specific epigenetic mechanism that regulates axonal regeneration of CNS axons, suggesting novel targets for clinical application.