SOD1G93A transgenic mouse CD4+ T cells mediate neuroprotection after facial nerve axotomy when removed from a suppressive peripheral microenvironment

Mesnard-Hoaglin, Nichole A.; Xin, Junping; Haulcomb, Melissa M.; Batka, Richard J.; Sanders, Virginia M.; Jones, Kathryn J.

doi:10.1016/j.bbi.2014.05.019

Cited by 10 publications

(16 citation statements)

References 34 publications

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“…The response to peripheral axotomy resembles the axonal die-back response, as both processes result in axonal disconnection from neuromuscular junctions in target muscle and after presynaptic stripping in the CNS. We, therefore, used axotomy as an investigative tool to delineate underlying molecular mechanisms that result in MN degeneration in pre-symptomatic mSOD1 mice (Mesnard et al 2010, 2011, 2013; Haulcomb et al 2014; Mesnard-Hoaglin et al 2014). The superimposition of facial nerve axotomy on pre-symptomatic mice allowed us to experimentally produce simultaneous die-back of a select MN population at a set time and for a controlled length of time post-axotomy.…”

Section: Use Of Axotomy As Tool In Understanding Als Pathogenesismentioning

confidence: 99%

“…Based upon the aforementioned studies, we hypothesized that a defective T cell population in the mSOD1 mouse could contribute to the immune dysfunction and MN cell death. To test this hypothesis, we conducted an extensive series of reconstitution experiments (Mesnard-Hoaglin et al 2014) utilizing both immunodeficient and mSOD1 mouse models. To our surprise, the results of that study indicate that mSOD1 mouse CD4 + T cells ARE ABLE TO mediate neuroprotection after facial nerve axotomy in immunodeficient mice when isolated from a suppressive mSOD1 peripheral splenic microenvironment.…”

Section: Use Of Axotomy As Tool In Understanding Als Pathogenesismentioning

confidence: 99%

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CD4 + T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease

Jones

Lovett-Racke

Walker

et al. 2015

J Neuroimmune Pharmacol

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We have established a physiologically relevant mechanism of CD4+ T cell-mediated neuroprotection involving axotomized wildtype (WT) mouse facial motoneurons (FMN) with significance in the treatment of amyotrophic lateral sclerosis (ALS), a fatal MN disease. Use of the transgenic mouse model of ALS involving expression of human mutant superoxide dismutase genes (SOD1G93A; abbreviated here as mSOD1) has accelerated basic ALS research. Superimposition of facial nerve axotomy (FNA) on the mSOD1 mouse during pre-symptomatic stages indicates that they behave like immunodeficient mice in terms of increased FMN loss and decreased functional recovery, through a mechanism that, paradoxically, is not inherent within the MN itself, but, instead, involves a defect in peripheral immune: CNS glial cell interactions. Our goal is to utilize our WT mouse model of immune-mediated neuroprotection after FNA as a template to elucidate how a malfunctioning peripheral immune system contributes to motoneuron cell loss in the mSOD1 mouse. This review will discuss potential immune defects in ALS, as well as provide an up-to-date understanding of how the CD4+ effector T cells provide neuroprotection to motoneurons through regulation of the central microglial and astrocytic response to injury. We will discuss an IL-10 cascade within the facial nucleus that requires a functional CD4+ T cell trigger for activation. The review will discuss the role of T cells in ALS, and our recent reconstitution experiments utilizing our model of T cell-mediated neuroprotection in WT vs mSOD1 mice after FNA. Identification of defects in neural:immune interactions could provide targets for therapeutic intervention in ALS.

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Section: Use Of Axotomy As Tool In Understanding Als Pathogenesismentioning

confidence: 99%

Section: Use Of Axotomy As Tool In Understanding Als Pathogenesismentioning

confidence: 99%

CD4 + T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease

Jones

Lovett-Racke

Walker

et al. 2015

J Neuroimmune Pharmacol

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“…No significant differences are observed in facial motoneuron counts of the control side, indicating that the genetic alterations do not impact baseline counts. Compared to the motoneuron survival in wild type mice (84% ± 2.0; Figure 1A,D), significant cell loss is observed in a mouse model of amyotrophic lateral sclerosis (SOD1 G93A ; 68% ± 1; Figure 1B,E) as well as the immunodeficient recombination-activating gene-2 knockout mouse (RAG-2-/-; 57% ± 2.5; Figure 1C,F) 27 . Figure 2 demonstrates the laser capture microdissection technique applied to the facial motor nucleus.…”

Section: Representative Resultsmentioning

confidence: 99%

Facial Nerve Axotomy in Mice: A Model to Study Motoneuron Response to Injury

Olmstead

Mesnard-Hoaglin

Batka

et al. 2015

JoVE

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The goal of this surgical protocol is to expose the facial nerve, which innervates the facial musculature, at its exit from the stylomastoid foramen and either cut or crush it to induce peripheral nerve injury. Advantages of this surgery are its simplicity, high reproducibility, and the lack of effect on vital functions or mobility from the subsequent facial paralysis, thus resulting in a relatively mild surgical outcome compared to other nerve injury models. A major advantage of using a cranial nerve injury model is that the motoneurons reside in a relatively homogenous population in the facial motor nucleus in the pons, simplifying the study of the motoneuron cell bodies. Because of the symmetrical nature of facial nerve innervation and the lack of crosstalk between the facial motor nuclei, the operation can be performed unilaterally with the unaxotomized side serving as a paired internal control. A variety of analyses can be performed postoperatively to assess the physiologic response, details of which are beyond the scope of this article. For example, recovery of muscle function can serve as a behavioral marker for reinnervation, or the motoneurons can be quantified to measure cell survival. Additionally, the motoneurons can be accurately captured using laser microdissection for molecular analysis. Because the facial nerve axotomy is minimally invasive and well tolerated, it can be utilized on a wide variety of genetically modified mice. Also, this surgery model can be used to analyze the effectiveness of peripheral nerve injury treatments. Facial nerve injury provides a means for investigating not only motoneurons, but also the responses of the central and peripheral glial microenvironment, immune system, and target musculature. The facial nerve injury model is a widely accepted peripheral nerve injury model that serves as a powerful tool for studying nerve injury and regeneration. Video LinkThe video component of this article can be found at

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“…Infiltrated T cells also assist in tissue recovery after injury. For instance, activated T cells reactive to specific antigens generated after nerve crush help to prevent further axonal degeneration (Moalem et al 1999;Yoles et al 2001;Mesnard-Hoaglin et al 2014).…”

Section: Neuroinflammationmentioning

confidence: 99%

Endogenous recovery after brain damage: molecular mechanisms that balance neuronal life/death fate

Tovar‐y‐Romo

Penagos-Puig

Ramírez-Jarquín

2015

Journal of Neurochemistry

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Neuronal survival depends on multiple factors that comprise a well-fueled energy metabolism, trophic input, clearance of toxic substances, appropriate redox environment, integrity of blood-brain barrier, suppression of programmed cell death pathways and cell cycle arrest. Disturbances of brain homeostasis lead to acute or chronic alterations that might ultimately cause neuronal death with consequent impairment of neurological function. Although we understand most of these processes well when they occur independently from one another, we still lack a clear grasp of the concerted cellular and molecular mechanisms activated upon neuronal damage that intervene in protecting damaged neurons from death. In this review, we summarize a handful of endogenously activated mechanisms that balance molecular cues so as to determine whether neurons recover from injury or die. We center our discussion on mechanisms that have been identified to participate in stroke, although we consider different scenarios of chronic neurodegeneration as well. We discuss two central processes that are involved in endogenous repair and that, when not regulated, could lead to tissue damage, namely, trophic support and neuroinflammation. We emphasize the need to construct integrated models of neuronal degeneration and survival that, in the end, converge in neuronal fate after injury.

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SOD1G93A transgenic mouse CD4+ T cells mediate neuroprotection after facial nerve axotomy when removed from a suppressive peripheral microenvironment

Cited by 10 publications

References 34 publications

CD4 + T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease

CD4 + T Cells and Neuroprotection: Relevance to Motoneuron Injury and Disease

Facial Nerve Axotomy in Mice: A Model to Study Motoneuron Response to Injury

Endogenous recovery after brain damage: molecular mechanisms that balance neuronal life/death fate

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