Role of the immune system in the maintenance of mouse facial motoneuron viability after nerve injury

Jones, Kathryn J.; Serpe, Craig J.; Byram, Susanna C.; DeBoy, Cynthia A.; Sanders, Virginia M.

doi:10.1016/j.bbi.2004.05.004

Cited by 49 publications

(57 citation statements)

References 29 publications

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“…CD4 + T lymphocytemediated autoimmune responses are vital in the pathogenesis of multiple sclerosis and, to some extent, Alzheimer's disease [17,18]. Alternatively, CNS-infiltrating activated CD4 + T lymphocytes promote facial motoneuron survival following axotomy injury [19], possibly via their brain-derived neurotrophic factor (BDNF) production [20]. The report that intraperitoneal injection of in vitro driven type 1 helper T (Th1) lymphocytes induced nociceptive hypersensitivity post CCI in athymic nude rats (rnu -/-), while type 2 helper T lymphocytes prevented the behavioral hypersensitivity in the heterozygous rnu +/-rats [8], provided initial evidence of the involvement of CD4 + T lymphocytes in neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

CNS‐infiltrating CD4⁺ T lymphocytes contribute to murine spinal nerve transection‐induced neuropathic pain

2008

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We previously reported leukocytic infiltration into the lumbar spinal cord in a rodent spinal nerve L5 transection (L5Tx) neuropathic pain model. Here, we further investigated the role of infiltrating T lymphocytes in the etiology of persistent pain following L5Tx. T lymphocyte-deficient nude mice showed no evident mechanical hypersensitivity after day 3 of L5Tx compared to wild-type BALB/c mice. Through FACS analysis, we determined that significant leukocytic infiltration (CD45 hi ) into the lumbar spinal cord peaked at day 7 post L5Tx. These infiltrating leukocytes contained predominantly CD4 + but not CD8 + T lymphocytes. B lymphocytes, natural killer cells and macrophages were not detected at day 7 post L5Tx. No differences in the activation of peripheral CD4 + T lymphocytes were detected in either the spleen or lumbar lymph nodes between L5Tx and sham surgery groups. Further, CD4 KO mice displayed significantly decreased mechanical hypersensitivity after day 7 of L5Tx, and adoptive transfer of CD4 + leukocytes reversed this effect. Decreased immunoreactivity of glial fibrillary acidic protein observed in CD4 KO mice post L5Tx indicated possible T lymphocyte-glial interactions. These results strongly support a contributing role of spinal cord-infiltrating CD4 + T lymphocytes versus peripheral CD4 + T lymphocytes in the maintenance of nerve injury-induced neuropathic pain.

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Section: Discussionmentioning

confidence: 99%

CNS‐infiltrating CD4⁺ T lymphocytes contribute to murine spinal nerve transection‐induced neuropathic pain

2008

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“…Glial cells residing in the damaged tissue are poised to initiate an inflammatory response that recruits leukocytes to the injured CNS. Infiltrating leukocytes may promote repair but retain the capacity to exacerbate injury-induced neuropathology (1)(2)(3). From a therapeutic standpoint, it is important to understand the signaling mechanisms that guide leukocytes to the damaged CNS.…”

mentioning

confidence: 99%

“…We have assessed the impact of MyD88 signaling on the innate response to stab injury in the entorhinal cortex (EC) 3 of mice and to the resulting axonal degeneration in the denervated hippocampus. This was achieved by using a stereotactic surgical model to localize mechanical damage to the EC of mice (15,(43)(44)(45).…”

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confidence: 99%

Signaling through MyD88 Regulates Leukocyte Recruitment after Brain Injury

Babcock

Toft-Hansen

Owens

2008

The Journal of Immunology

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Injury to the CNS provokes an innate inflammatory reaction that engages infiltrating leukocytes with the capacity to repair and/or exacerbate tissue damage. The initial cues that orchestrate leukocyte entry remain poorly defined. We have used flow cytometry to investigate whether MyD88, an adaptor protein that transmits signals from TLRs and receptors for IL-1 and IL-18, regulates leukocyte infiltration into the stab-injured entorhinal cortex (EC) and into sites of axonal degeneration in the denervated hippocampus. We have previously established the kinetics of leukocyte entry into the denervated hippocampus. We now show that significant leukocyte entry into the EC occurs within 3–12 h of stab injury. Whereas T cells showed small, gradual increases over 8 days, macrophage infiltration was pronounced and peaked within 12–24 h. MyD88 deficiency significantly reduced macrophage and T cell recruitment to the stab-injured EC and the denervated hippocampus at 5 days post-injury. Whereas macrophage and T cell entry remained impaired into the denervated hippocampus of MyD88-deficient mice at 8 days, leukocyte infiltration into the stab-injured EC was restored to levels observed in wild-type mice. Transcripts for TNF-α, IL-1β, and CCL2, which increased >50-fold after stab injury in C57BL/6 mice at the time of peak expression, were severely reduced in injured MyD88 knockout mice. Leukocyte recruitment and gene expression were unaffected in TLR2-deficient or TLR4 mutant mice. No significant differences in gene expression were observed in mice lacking IL-1R or IL-18R. These data show that MyD88-dependent signaling mediates proinflammatory gene expression and leukocyte recruitment after CNS injury.

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“…In pathogenic states such as experimental autoimmune encephalomyelitis (EAE) and infection, the presence of T cells in the brain can have detrimental effects (Martino and Hartung, 1999;Nau and Bruck, 2002), while in other contexts, T cells have been shown to act in concert with glial cells to promote neuroregeneration (Byram, et al, 2004, Martino and Hartung, 1999, Nau and Bruck, 2002, Raivich, et al, 1998, Schwartz, 2003. Studies have demonstrated the effectiveness of T cells in preventing neuronal loss following injury (Armstrong, et al, 2004, Jones, et al, 2005, Schwartz and Moalem, 2001). To date, research has focused on elucidating the role of T cells in preventing initial neuronal death or slowing the rate of neurodegeneration and gradual neuronal loss following facial nerve axotomy (Jones, et al, 2005, Serpe, et al, 1999, Serpe, et al, 2000.…”

Section: Introductionmentioning

confidence: 99%

“…Studies have demonstrated the effectiveness of T cells in preventing neuronal loss following injury (Armstrong, et al, 2004, Jones, et al, 2005, Schwartz and Moalem, 2001). To date, research has focused on elucidating the role of T cells in preventing initial neuronal death or slowing the rate of neurodegeneration and gradual neuronal loss following facial nerve axotomy (Jones, et al, 2005, Serpe, et al, 1999, Serpe, et al, 2000. Given that a substantial number of facial motor neurons undergo atrophy following axotomy and that the atrophied state of these neurons is reversible by reinjury, T cells may also be involved in mediating the reversal of neuronal atrophy following re-injury.…”

Section: Introductionmentioning

confidence: 99%

Immunodeficiency impairs re-injury induced reversal of neuronal atrophy: Relation to T cell subsets and microglia

Ha¹,

Huang²,

Parikh³

et al. 2007

Experimental Neurology

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Following facial nerve resection in the mouse, a substantial number of neurons reside in an atrophied state (characterized by cell shrinkage and decreased ability to uptake Nissl stain), which can be reversed by re-injury. The mechanisms mediating the reversal of neuronal atrophy remain unclear. Although T cells have been shown to prevent neuronal loss following peripheral nerve injury, it was unknown whether T cells play a role in mediating the reversal of axotomy-induced neuronal atrophy. Thus, we used a facial nerve re-injury model to test the hypothesis that the reversal of neuronal atrophy would be impaired in recombinase activating gene-2 knockout (RAG-2 KO) mice, which lack functional T and B cells. Measures of neuronal survival were compared in the injured facial motor nucleus (FMN) of RAG-2 KO and wild-type (WT) mice that received a resection of the right facial nerve followed by re-injury of the same nerve 10 weeks later ("chronic resection + re-injury") or a resection of the right facial nerve followed by sham re-injury of the same nerve 10 weeks later ("chronic resection + sham"). We recently demonstrated that prior exposure to neuronal injury elicited a marked increase in T cell trafficking indicative of a T cell memory response when the contralateral FMN was injured later in adulthood. We examined if such a T cell memory response would also occur in the current re-injury model. RAG-2 KO mice showed no reversal of neuronal atrophy whereas WT mice showed a robust response. The reversal of atrophy in WT mice was not accompanied by a T cell memory response. Although the number of CD4 + and CD8 + T cells in the injured FMN did not differ from each other, double-negative T cells appear to be recruited in response to neuronal injury. Re-injury did not result in increased expression of MHC2 by microglia. Our findings suggest that T cells may be involved in reversing the axotomy-induced atrophy of injured neurons.

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Role of the immune system in the maintenance of mouse facial motoneuron viability after nerve injury

Cited by 49 publications

References 29 publications

CNS‐infiltrating CD4⁺ T lymphocytes contribute to murine spinal nerve transection‐induced neuropathic pain

CNS‐infiltrating CD4⁺ T lymphocytes contribute to murine spinal nerve transection‐induced neuropathic pain

Signaling through MyD88 Regulates Leukocyte Recruitment after Brain Injury

Immunodeficiency impairs re-injury induced reversal of neuronal atrophy: Relation to T cell subsets and microglia

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Role of the immune system in the maintenance of mouse facial motoneuron viability after nerve injury

Cited by 49 publications

References 29 publications

CNS‐infiltrating CD4+ T lymphocytes contribute to murine spinal nerve transection‐induced neuropathic pain

CNS‐infiltrating CD4+ T lymphocytes contribute to murine spinal nerve transection‐induced neuropathic pain

Signaling through MyD88 Regulates Leukocyte Recruitment after Brain Injury

Immunodeficiency impairs re-injury induced reversal of neuronal atrophy: Relation to T cell subsets and microglia

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CNS‐infiltrating CD4⁺ T lymphocytes contribute to murine spinal nerve transection‐induced neuropathic pain

CNS‐infiltrating CD4⁺ T lymphocytes contribute to murine spinal nerve transection‐induced neuropathic pain