Neuroprotective effect of the immune system in a mouse model of severe dysmyelinating hereditary neuropathy: enhanced axonal degeneration following disruption of the RAG-1 gene

Berghoff, Martin; Samsam, Mohtashem; Müller, Marcus; Kobsar, Igor; Toyka, Klaus V.; Kiefer, Reinhard; Mäurer, Mathias; Martini, Rudolf

doi:10.1016/j.mcn.2004.09.001

Cited by 31 publications

(26 citation statements)

References 47 publications

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“…In fact, adaptive immunodeficiency may increase axonal degeneration, as evidenced by the lower density of axons in the Rag -/- animals. These data agreed with recent work showing greater axonal degeneration in Rag -/- mice in a model of dysmyelination due to mutations in myelin basic protein [29]. In the study by Berghoff, et al, macrophages were retained in the nerve for longer periods than immunocompetent animals, but myelin disruption was not significantly different between the immunocompetent and immunodeficient dysmyelinated animals [29].…”

Section: Resultssupporting

confidence: 91%

Deficiency of adaptive immunity does not interfere with Wallerian degeneration

Cashman

Höke²

2017

PLoS ONE

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Following injury, distal axons undergo the process of Wallerian degeneration, and then cell debris is cleared to create a permissive environment for axon regeneration. The innate and adaptive immune systems are believed to be critical for facilitating the clearance of myelin and axonal debris during this process. However, immunodeficient animal models are regularly used in transplantation studies investigating cell therapies to modulate the degenerative/regenerative response. Given the importance of the immune system in preparing a permissive environment for regeneration by clearing debris, animals lacking, in part or in full, a functional immune system may have an impaired ability to regenerate due to poor myelin clearance, and may, thus, be poor hosts to study modulators of regeneration and degeneration. To study this hypothesis, three different mouse models with impaired adaptive immunity were compared to wild type animals in their ability to degenerate axons and clear myelin debris one week following sciatic nerve transection. Immunofluorescent staining for axons and quantitation of axon density with nerve histomorphometry of the distal stump showed no consistent discrepancy between immunodeficient and wild type animals, suggesting axons tended to degenerate equally between the two groups. Debris clearance was assessed by macrophage density and relative myelin basic protein expression within the denervated nerve stump, and no consistent impairment of debris clearance was found. These data suggested deficiency of the adaptive immune system does not have a substantial effect on axon degeneration one week following axonal injury.

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Section: Resultssupporting

confidence: 91%

Deficiency of adaptive immunity does not interfere with Wallerian degeneration

Cashman

Höke²

2017

PLoS ONE

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“…A completely different set of changes was found in dysmyelinating P0 2/2 mice. In the P0 null mutants, macrophages usually do not penetrate into the endoneurial tubes, but appear to accumulate in the endoneurium near the degenerating axons, which acquire the appearance of degenerating end bulbs (Berghoff et al, 2005;Ey et al, 2007). The interactions between mutant Schwann cells and macrophages in P0 2/2 have not been characterized yet, and will, therefore, not be considered any further.…”

Section: Macrophages Increase In Number and Associate With Myelin In mentioning

confidence: 99%

Interactions between Schwann cells and macrophages in injury and inherited demyelinating disease

Martini

Fischer

López-Vales

et al. 2008

Glia

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270

239

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In this article we first discuss the factors that regulate macrophage recruitment, activation, and myelin phagocytosis during Wallerian degeneration and some of the factors involved in the termination of inflammation at the end of the period of Wallerian degeneration after peripheral nerve injuries. In particular, we deal with the early events that trigger chemokine and cytokine expression; the role of phospholipase A 2 in initiating the breakdown of compact myelin, and chemokine, cytokine expression; and the role of MCP-1, MIP-1a, and IL-1b in macrophage recruitment and myelin phagocytosis. We also discuss how inflammation may be switched off and the recently identified role of the Nogo receptor on activated macrophages in the clearance of these cells from the injured nerve. In the second half of the article we focus on the role of certain Schwann cell borne cytokines and chemokines, such as M-CSF and MCP-1 as well as intracellular signaling that regulate their expression in animal models of inherited demyelinating disease. Additionally, we present the preservation of sensory nerves fibers from macrophage attack in these animal models as a challenging paradigm for the development of putative treatment approaches. Finally, we also discuss the similarities and differences in these Schwann cell-macrophage responses in injury-induced Wallerian degeneration and inherited demyelinating diseases. Knowledge of the molecular mechanisms underlying Schwann cell-macrophage interaction under pathological conditions is an important prerequisite to develop effective treatment strategies for various peripheral nerve disorders. V V C

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“…[1][2][3][4][5][6][7] A possible molecular explanation for these findings is that the nervous and immune systems engage in intense cross-talk. 8 Both systems produce a range of factors (e.g., cytokines for the immune system and neurotrophic factors for the CNS) that modulate cell growth and differentiation.…”

mentioning

confidence: 99%

Dual role of inflammation in CNS disease

Hohlfeld¹,

Kerschensteiner²,

Meinl³

2007

Neurology

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Inflammatory responses in the CNS have usually been perceived to cause or contribute to neuron injury. However, emerging evidence suggests that inflammatory reactions can also be neuroprotective. The nervous and immune systems employ overlapping mechanisms and shared mediators that promote cross-talk between the two systems. Immune cells, for example, produce not only neurodestructive molecules but also factors that can support neuroaxonal growth, survival, and plasticity. This might explain why inflammatory reactions may contribute to both injury and protection of neurons. The dual role of CNS inflammation also has important therapeutic implications that are only beginning to be explored.

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Neuroprotective effect of the immune system in a mouse model of severe dysmyelinating hereditary neuropathy: enhanced axonal degeneration following disruption of the RAG-1 gene

Cited by 31 publications

References 47 publications

Deficiency of adaptive immunity does not interfere with Wallerian degeneration

Deficiency of adaptive immunity does not interfere with Wallerian degeneration

Interactions between Schwann cells and macrophages in injury and inherited demyelinating disease

Dual role of inflammation in CNS disease

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