Exacerbation of Facial Motoneuron Loss after Facial Nerve Transection in Severe Combined Immunodeficient (<i>scid</i>) Mice

Serpe, Craig J.; Kohm, Adam P.; Huppenbauer, Christopher B.; Sanders, Virginia M.; Jones, Kathryn J.

doi:10.1523/jneurosci.19-11-j0004.1999

Cited by 150 publications

(141 citation statements)

References 27 publications

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“…For example, less CNS regeneration is observed after mechanical trauma and more severe dysfunction results after cytokine induced injury in mice deficient for T cells or antigen-presenting cells [51][52][53]. As yet the mechanism of T cell mediated protection is being explored.…”

Section: Can Inflammation Be Neuroprotective?mentioning

confidence: 99%

“…This inflammation was initially speculated to be at best benign but more likely a contributing cause of motoneuron degeneration. Surprisingly, in the absence of CD4+T cells, motoneuron degeneration was found to be much more rapid and severe [51]. Using bone marrow chimeric mice, animals were generated in which either only microglia or only hematogenous immune cells could act as antigen-presenting cells [58].…”

Section: What Determines Whether T Cells Are Neuroprotective Versus Nmentioning

confidence: 99%

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The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival

Carson

Thrash

Walter

2006

Clinical Neuroscience Research

234

156

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Neuroinflammation is a complex integration of the responses of all cells present within the CNS, including the neurons, macroglia, microglia and the infiltrating leukocytes. The initiating insult, environmental factors, genetic background and age/past experiences all combine to modulate the integrated response of this complex neuroinflammatory circuit. Here, we explore how these factors interact to lead to either neuroprotective versus neurotoxic inflammatory responses. We specifically focus on microglia and astrocytic regulation of autoreactive T cell responses.

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Section: Can Inflammation Be Neuroprotective?mentioning

confidence: 99%

Section: What Determines Whether T Cells Are Neuroprotective Versus Nmentioning

confidence: 99%

The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival

Carson

Thrash

Walter

2006

Clinical Neuroscience Research

234

156

View full text Add to dashboard Cite

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“…The effect of T cells in the central nervous system (CNS) appears to be context-dependent, as their presence has been shown to promote neuronal survival following certain types of injuries or, conversely, contribute to CNS pathology, such as in experimental autoimmune encephalomyelitis (EAE) and infection (Byram et al, 2004;Martino and Hartung, 1999;Nau and Bruck, 2002;Schwartz, 2001;Serpe et al, 1999). Peripheral transection of the facial nerve in adult mice induces retrograde neuronal cell loss in the facial motor nucleus (FMN) that is accompanied by a site-specific infiltration of T cells across an intact blood-brain-barrier to the injured motor neurons (Moran and Graeber, 2004;Raivich et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Influence of injury severity on the rate and magnitude of the T lymphocyte and neuronal response to facial nerve axotomy

Ha¹,

Parikh²,

Huang³

et al. 2008

Journal of Neuroimmunology

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The temporal relationship between severity of peripheral axonal injury and T lymphocyte trafficking to the neuronal cell bodies of origin in the brain has been unclear. We sought to test the hypothesis that greater neuronal death induced by disparate forms of peripheral nerve injury would result in differential patterns of T cell infiltration and duration at the cell bodies of origin in the brain and that these measures would correlate with the magnitude of neuronal death over time and cumulative neuronal loss. To test this hypothesis, we compared the time course of CD3 + T cell infiltration and neuronal death (assessed by CD11b + perineuronal microglial phagocytic clusters) following axonal crush versus axonal resection injuries, two extreme variations of facial nerve axotomy that result in mild versus severe neuronal loss, respectively, in the facial motor nucleus. We also quantified the number of facial motor neurons present at 49 days post-injury to determine whether differences in the levels of neuronal death between nerve crush and resection correlated with differences in cumulative neuronal loss. Between 1-7 days post-injury when levels of neuronal death were minimal, we found that the rate of accumulation and magnitude of the T cell response was similar following nerve crush and resection. Differences in the T cell response were apparent by 14 days post-injury when the level of neuronal death following resection was substantially greater than that seen in crush injury. For nerve resection, the peak of neuronal death at 14 days post-resection was followed by a maximal T cell response one week later at 21 days. Differences in the level of neuronal death between the two injuries across the time course tested reflected differences in cumulative neuronal loss at 49 days post-injury. Altogether, these data suggest that the trafficking of T cells to the injured FMN is dependent upon the intensity of peripheral nerve injury and associated neuronal death.

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“…In certain contexts, T cells can provide neuroprotection to axotomized motoneurons. Severe combined immunodeficient (SCID) and recombinase activating gene-2 (RAG-2) deficient mice, which lack functionally mature T and B lymphocytes, develop a profound loss of facial motor neurons following axotomy and the loss of regenerative capacity is time-dependently prevented when normal lymphocytes are adoptively transferred prior to axotomy [16,23,24]. The signals that draw T cells to the injured cell bodies in the FMN are presumed to be chemokines and chemoattractant cytokines, although experimental studies addressing this question are lacking.…”

mentioning

confidence: 99%

IL-15 and IL-15Rα gene deletion: Effects on T lymphocyte trafficking and the microglial and neuronal responses to facial nerve axotomy

Huang

Petitto

2007

Neuroscience Letters

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IL-15 is a potent T cell chemoattractant, and this cytokine and its unique α subunits, IL-15Rα, can modify immune cell expression of several T cell chemokines and their receptors. Facial nerve axotomy in mice leads to T cell migration across an intact blood-brain-barrier (BBB), and under certain conditions T cells can provide neuroprotection to injured neurons in the facial motor nucleus (FMN). Although chemokines and chemoattractant cytokines are thought to be responsible for T cell migration to the injured cell bodies, data addressing this question are lacking. This study tested the hypothesis that T cell homing to the axotomized FMN would be impaired in knockout (KO) mice with the IL-15 and IL-15Rα genes deleted, and sought to determine if microglial responsiveness and motoneuron death are affected. Both IL-15KO and IL-15RαKO mice exhibited a marked reduction in CD3 + T cells and had fewer MHC2 + activated microglia in the injured FMN than their respective WT controls at day 14 post-axotomy. Although there was a relative absence of T cell recruitment into the axotomized FMN in both knockout strains, IL-15RαKO mice had five times more motoneuron death (characterized by perineuronal microglial clusters engulfing dead motoneurons) than their WT controls, whereas dead neurons in IL-15KO did not differ from their WT controls. Further studies are needed to dissect the mechanisms that underlie these observations (e.g., central vs. peripheral immune contributions).IL-15 and IL-2 are members of the 4α-helix bundle family of cytokines that share the same constitutively expressed pair of signal transducing β and γ receptor subunits, but exhibit high affinity binding to unique α subunits (e.g., IL-15Rα) that confer specificity for each cytokine. Mouse microglia express IL-15 and IL-15Rα [5], and human astrocytes and neural cell lines (e.g., neuroblastoma cells) also express IL-15 mRNA [11,20]. IL-15 is a potent T cell chemoattractant (Wilkinson and Liew, 1995). IL-15 and IL-15Rα can modify the expression of T cell chemoattractants including MCP-1, RANTES, and IP-10, chemokines and their receptors that have been implicated in autoimmune T cell infiltration of the CNS [1,2,8,15].T lymphocytes migrate in and out of the brain and other nonlymphoid organs, and can be found in very small numbers in the brain under normal physiological conditions [3,6,7]. Facial nerve axotomy in mice leads to T cell migration across an intact blood-brain-barrier (BBB) where

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Exacerbation of Facial Motoneuron Loss after Facial Nerve Transection in Severe Combined Immunodeficient (scid) Mice

Cited by 150 publications

References 27 publications

The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival

The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival

Influence of injury severity on the rate and magnitude of the T lymphocyte and neuronal response to facial nerve axotomy

IL-15 and IL-15Rα gene deletion: Effects on T lymphocyte trafficking and the microglial and neuronal responses to facial nerve axotomy

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