scholarly journals Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages is necessary for functional spinal cord regeneration in zebrafish

2018 ◽  
Author(s):  
Themistoklis M. Tsarouchas ◽  
Daniel Wehner ◽  
Leonardo Cavone ◽  
Tahimina Munir ◽  
Marcus Keatinge ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Immune Cells ◽  
Dynamic Control ◽  
Spinal Cord Regeneration ◽  
Tnf Α ◽  
Cord Injury ◽  
Functional Regeneration ◽  
Necessary And Sufficient ◽  
Early Regeneration

ABSTRACTSpinal cord injury leads to a massive response of innate immune cells (microglia, macrophages, neutrophils) both, in non-regenerating mammals and in successfully regenerating zebrafish, but the role of these immune cells in functional spinal cord regeneration in zebrafish has not been addressed. Here we show that inhibiting inflammation reduces and promoting it accelerates axonal regeneration in larval zebrafish. Mutant analyses show that peripheral macrophages, but not neutrophils or microglia, are necessary and sufficient for full regeneration. Macrophage-less irf8 mutants show prolonged inflammation with elevated levels of Il-1β and Tnf-α. Decreasing Il-1β levels or number of Il-1β+ neutrophils rescues functional regeneration in irf8 mutants. However, during early regeneration, interference with Il-1β function impairs regeneration in irf8 and wildtype animals. Inhibiting Tnf-α does not rescue axonal growth in irf8 mutants, but impairs it in wildtype animals, indicating a pro-regenerative role of Tnf-α. Hence, inflammation is tightly and dynamically controlled by macrophages to promote functional spinal cord regeneration in zebrafish.

Cellular Dynamics during Spinal Cord Regeneration in Larval Zebrafish

2019 ◽  
Vol 41 (1-2) ◽  
pp. 112-122 ◽  
Author(s):  
Consuelo Anguita-Salinas ◽  
Mario Sánchez ◽  
Rodrigo A. Morales ◽  
María Laura Ceci ◽  
Diego Rojas-Benítez ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Immune Cells ◽  
Cell Types ◽  
Regenerative Process ◽  
Spinal Cord Regeneration ◽  
Cord Injury ◽  
Complete Reversal ◽  
Transgenic Lines ◽  
Functional Regeneration

The study of spinal cord regeneration using diverse animal models, which range from null to robust regenerative capabilities, is imperative for understanding how regeneration evolved and, eventually, to treat spinal cord injury and paralysis in humans. In this study, we used electroablation to fully transect the spinal cord of zebrafish larvae (3 days postfertilization) and examined regeneration of the tissue over time. We used transgenic lines to follow immune cells, oligodendrocytes, and neurons in vivo during the entire regenerative process. We observed that immune cells are recruited to the injury site, oligodendrocytes progenitor cells (olig2-expressing cells) invade, and axons cross the gap generated upon damage from anterior to reinnervate caudal structures. Together with the recovery of cell types and structures, a complete reversal of paralysis was observed in the lesioned larvae indicating functional regeneration. Finally, using transplantation to obtain mosaic larvae with single-labeled neurons, we show that severed spinal axons exhibited varying regenerative capabilities and plasticity depending on their original dorsoventral position in the spinal cord.

scholarly journals Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages in zebrafish spinal cord regeneration

2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Themistoklis M. Tsarouchas ◽  
Daniel Wehner ◽  
Leonardo Cavone ◽  
Tahimina Munir ◽  
Marcus Keatinge ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Proinflammatory Cytokines ◽  
Dynamic Control ◽  
Spinal Cord Regeneration ◽  
Tnf Α

scholarly journals Spinal cord regeneration: A brief overview of present scenario and a sneak peek into the future

2021 ◽  
Author(s):  
Ekta Srivastava ◽  
Anamika Singh ◽  
Ashok Kumar
Keyword(s):  
Spinal Cord ◽  
Treatment Approach ◽  
Current Treatment ◽  
The Body ◽  
Spinal Cord Regeneration ◽  
Cord Injury ◽  
Regeneration Capability ◽  
Further Development ◽  
Combinatorial Treatment

Central nervous system (CNS) portrays appreciable complexity in developing from a neural tube to controlling major functions of the body and orchestrated co-ordination in maintaining its homeostasis. Any insult or pathology to such an organized tissue leads to a plethora of events ranging from local hypoxia, ischemia, oxidative stress to reactive gliosis and scarring. Despite unravelling the pathophysiology of spinal cord injury (SCI) and linked cellular and molecular mechanism, the over exhaustive inflammatory response at the site of injury, limited intrinsic regeneration capability of CNS, and the dual role of glial scar halts the expected accomplishment. The review discusses major current treatment approaches for traumatic SCI, addressing their limitation and scope for further development in the field under three main categories- neuroprotection, neuro-regeneration, and neuroplasticity. We further propose that a multi-disciplinary combinatorial treatment approach exploring any two or all three heads simultaneously could alleviate the inhibitory milieu and ameliorate functional recovery.

scholarly journals The Role of Microglia in Modulating Neuroinflammation after Spinal Cord Injury

2021 ◽  
Vol 22 (18) ◽  
pp. 9706
Author(s):  
Sydney Brockie ◽  
James Hong ◽  
Michael G. Fehlings
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Immune Cells ◽  
Lesion Site ◽  
Surface Receptors ◽  
Cord Injury ◽  
Numerous Cell ◽  
The Central Nervous System ◽  
Temporal Profiles

The pathobiology of traumatic and nontraumatic spinal cord injury (SCI), including degenerative myelopathy, is influenced by neuroinflammation. The neuroinflammatory response is initiated by a multitude of injury signals emanating from necrotic and apoptotic cells at the lesion site, recruiting local and infiltrating immune cells that modulate inflammatory cascades to aid in the protection of the lesion site and encourage regenerative processes. While peripheral immune cells are involved, microglia, the resident immune cells of the central nervous system (CNS), are known to play a central role in modulating this response. Microglia are armed with numerous cell surface receptors that interact with neurons, astrocytes, infiltrating monocytes, and endothelial cells to facilitate a dynamic, multi-faceted injury response. While their origin and essential nature are understood, their mechanisms of action and spatial and temporal profiles warrant extensive additional research. In this review, we describe the role of microglia and the cellular network in SCI, discuss tools for their investigation, outline their spatiotemporal profile, and propose translationally-relevant therapeutic targets to modulate neuroinflammation in the setting of SCI.

scholarly journals The Function of FGFR1 Signalling in the Spinal Cord: Therapeutic Approaches Using FGFR1 Ligands after Spinal Cord Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-13 ◽  
Author(s):  
Barbara Haenzi ◽  
Lawrence D. F. Moon
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Sensory Function ◽  
Partial Recovery ◽  
Nerve Grafts ◽  
Cord Injury ◽  
Show Evidence ◽  
Peripheral Nerve Grafts ◽  
Functional Regeneration

Extensive research is ongoing that concentrates on finding therapies to enhance CNS regeneration after spinal cord injury (SCI) and to cure paralysis. This review sheds light on the role of the FGFR pathway in the injured spinal cord and discusses various therapies that use FGFR activating ligands to promote regeneration after SCI. We discuss studies that use peripheral nerve grafts or Schwann cell grafts in combination with FGF1 or FGF2 supplementation. Most of these studies show evidence that these therapies successfully enhance axon regeneration into the graft. Further they provide evidence for partial recovery of sensory function shown by electrophysiology and motor activity evidenced by behavioural data. We also present one study that indicates that combination with additional, synergistic factors might further drive the system towards functional regeneration. In essence, this review summarises the potential of nerve and cell grafts combined with FGF1/2 supplementation to improve outcome even after severe spinal cord injury.

scholarly journals Transneuronal delivery of designer-cytokine enables functional recovery after complete spinal cord injury

2019 ◽  
Author(s):  
Marco Leibinger ◽  
Charlotte Zeitler ◽  
Philipp Gobrecht ◽  
Anastasia Andreadaki ◽  
Dietmar Fischer
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Brain Stem ◽  
Functional Recovery ◽  
Spinal Cord Regeneration ◽  
Serotonergic Neurons ◽  
Cord Injury ◽  
Functional Regeneration ◽  
Complete Spinal Cord Injury ◽  
The Brain

AbstractSpinal cord injury (SCI) often causes severe and permanent disabilities. The current study uses a transneuronal approach to stimulate spinal cord regeneration by AAV-hyper-IL-6 (hIL-6) application after injury. While preinjury PTEN knockout in cortical motoneurons fails to improve functional recovery after complete spinal cord crush, a single, postinjury injection of hIL-6 into the sensorimotor cortex markedly promotes axon regeneration in the corticospinal and, remarkably, raphespinal tracts enabling significant locomotion recovery of both hindlimbs. Moreover, transduced cortical motoneurons directly innervate serotonergic neurons in both sides of the raphe nuclei equally, enabling the synaptic release of hIL-6 and the transneuronal stimulation of raphe neurons in the brain stem. Functional recovery depends on the regeneration of serotonergic neurons as their degeneration induced by a toxin abolishes the hIL-6-mediated recovery. Thus, the transneuronal application of highly potent cytokines enables functional regeneration by stimulating neurons in the deep brain stem that are otherwise challenging to access, yet highly relevant for functional recovery after SCI.

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