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Kathryn J Jones - One of the best experts on this subject based on the ideXlab platform.
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cd4 t cell expression of the il 10 receptor is necessary for Facial motoneuron survival after axotomy
Journal of Neuroinflammation, 2020Co-Authors: Elizabeth M Runge, Deborah O Setter, Felicia M Kennedy, Virginia M Sanders, Abhirami K Iyer, Kathryn J JonesAbstract:After peripheral nerve transection, Facial motoneuron (FMN) survival depends on an intact CD4+ T cell population and a central source of interleukin-10 (IL-10). However, it has not been determined previously whether CD4+ T cells participate in the central neuroprotective IL-10 cascade after Facial nerve axotomy (FNA). Immunohistochemical labeling of CD4+ T cells, pontine vasculature, and central microglia was used to determine whether CD4+ T cells cross the blood-brain barrier and enter the Facial Motor Nucleus (FMNuc) after FNA. The importance of IL-10 signaling in CD4+ T cells was assessed by performing adoptive transfer of IL-10 receptor beta (IL-10RB)-deficient CD4+ T cells into immunodeficient mice prior to injury. Histology and qPCR were utilized to determine the impact of IL-10RB-deficient T cells on FMN survival and central gene expression after FNA. Flow cytometry was used to determine whether IL-10 signaling in T cells was necessary for their differentiation into neuroprotective subsets. CD4+ T cells were capable of crossing the blood-brain barrier and associating with reactive microglial nodules in the axotomized FMNuc. Full induction of central IL-10R gene expression after FNA was dependent on CD4+ T cells, regardless of their own IL-10R signaling capability. Surprisingly, CD4+ T cells lacking IL-10RB were incapable of mediating neuroprotection after axotomy and promoted increased central expression of genes associated with microglial activation, antigen presentation, T cell co-stimulation, and complement deposition. There was reduced differentiation of IL-10RB-deficient CD4+ T cells into regulatory CD4+ T cells in vitro. These findings support the interdependence of IL-10- and CD4+ T cell-mediated mechanisms of neuroprotection after axotomy. CD4+ T cells may potentiate central responsiveness to IL-10, while IL-10 signaling within CD4+ T cells is necessary for their ability to rescue axotomized motoneuron survival. We propose that loss of IL-10 signaling in CD4+ T cells promotes non-neuroprotective autoimmunity after FNA.
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Facial nerve axotomy in mice a model to study motoneuron response to injury
Journal of Visualized Experiments, 2015Co-Authors: Deborah Olmstead, Whitney M Miller, Melissa M Haulcomb, Nichole A Mesnardhoaglin, Richard J Batka, Kathryn J JonesAbstract: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.
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differential gene expression in the axotomized Facial Motor Nucleus of presymptomatic sod1 mice
The Journal of Comparative Neurology, 2011Co-Authors: Virginia M Sanders, Nichole A Mesnard, Kathryn J JonesAbstract:Previously, we compared molecular profiles of one population of wild-type (WT) mouse Facial motoneurons (FMNs) surviving with FMNs undergoing significant cell death after axotomy. Regardless of their ultimate fate, injured FMNs respond with a vigorous pro-survival/regenerative molecular response. In contrast, the neuropil surrounding the two different injured FMN populations contained distinct molecular differences that support a causative role for glial and/or immune-derived molecules in directing contrasting responses of the same cell types to the same injury. In the current investigation, we utilized the Facial nerve axotomy model and a presymptomatic amyotrophic lateral sclerosis (ALS) mouse (SOD1) model to experimentally mimic the axonal die-back process observed in ALS pathogenesis without the confounding variable of disease onset. Pre-symptomatic SOD1 mice had a significant decrease in FMN survival compared with WT, which suggests an increased susceptibility to axotomy. Laser microdissection was used to accurately collect uninjured and axotomized Facial Motor nuclei of WT and presymptomatic SOD1 mice for mRNA expression pattern analyses of pro-survival/pro-regeneration genes, neuropil-specific genes, and genes involved in or responsive to the interaction of FMNs and non-neuronal cells. Axotomized pre-symptomatic SOD1 FMNs displayed a dynamic pro-survival/regenerative response to axotomy, similar to WT, despite increased cell death. However, significant differences were revealed when the axotomy-induced gene expression response of presymptomatic SOD1 neuropil was compared with WT. We propose that the increased susceptibility of presymptomatic SOD1 FMNs to axotomy-induced cell death and, by extrapolation, disease progression, is not intrinsic to the motoneuron, but rather involves a dysregulated response by non-neuronal cells in the surrounding neuropil.
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effects of Facial nerve axotomy on th2 and th1 associated chemokine expression in the Facial Motor Nucleus of wild type and presymptomatic msod1 mice
Journal of Neuroimmunology, 2009Co-Authors: Derek A Wainwright, Virginia M Sanders, Nichole A Mesnard, Junping Xin, Christine M Politis, Kathryn J JonesAbstract:We have previously demonstrated a neuroprotective mechanism of Facial motoneuron (FMN) survival after Facial nerve axotomy that is dependent on CD4(+) Th2 cell interaction with peripheral antigen-presenting cells, as well as CNS resident microglia. To investigate this mechanism, we chose to study the Th2-associated chemokine, CCL11, and Th1-associated chemokine, CXCL11, in wild-type and presymptomatic mSOD1 mice after Facial nerve axotomy. In this report, the results indicate that CCL11 is constitutively expressed in the uninjured Facial Motor Nucleus, but CXCL11 is not expressed at all. Facial nerve axotomy induced a shift in CCL11 expression from FMN to astrocytes, whereas CXCL11 was induced in FMN. Differences in the number of CCL11- and CXCL11-expressing cells were observed between WT and mSOD1 mice after Facial nerve axotomy.
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effects of Facial nerve axotomy on th2 associated and th1 associated chemokine mrna expression in the Facial Motor Nucleus of wild type and presymptomatic sod1 mice
Journal of neurodegeneration & regeneration, 2009Co-Authors: Derek A Wainwright, Virginia M Sanders, Nichole A Mesnard, Junping Xin, Kathryn J JonesAbstract:The authors have previously demonstrated a neuroprotective mechanism of Facial motoneuron (FMN) survival after Facial nerve transection that is dependent on CD4(+)T helper 2 (Th2) cell interactions with peripheral antigen presenting cells, as well as central nervous system (CNS) resident microglia. Pituitary adenylyl cyclase activating polypeptide is expressed by injured FMN and increases Th2-associated chemokine expression in cultured murine microglia. Collectively, these data suggest a model involving CD4(+) Th2 cell migration to the Facial Motor Nucleus after injury via microglial expression of Th2-associated chemokines. In this study, the authors tested the hypothesis that Th2-associated chemokine expression occurs in the Facial Motor Nucleus after Facial nerve axotomy at the stylomastoid foramen. Initial microarray analysis of Th2-associated and Th1-associated chemokine mRNA levels was accomplished after Facial nerve axotomy in wild type (WT) and presymptomatic mutant superoxide dismutase 1 (mSOD1) [model of familial amyotrophic lateral sclerosis (ALS)] mice. Based on that initial microarray analysis, the Th2-associated chemokine, CCL11, and Th1-associated chemokine, CXCL11, were further analyzed by RT-PCR. The results indicate that Facial nerve injury predominantly increases Th2-associated chemokine, but not Th1-associated chemokine mRNA levels in the mouse Facial Motor Nucleus. Interestingly, no differences were detected between WT and mSOD1 mice for CCL11 and CXCL11 after injury. These data provide a basis for further investigation into Th2-associated chemokine expression in the Facial Motor Nucleus after FMN injury, which may lead to more specifically targeted therapeutics in motoneuron diseases, such as ALS.
G Raivich - One of the best experts on this subject based on the ideXlab platform.
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major histocompatibility complex mhc2 perivascular macrophages in the axotomized Facial Motor Nucleus are regulated by receptors for interferon γ ifnγ and tumor necrosis factor tnf
Neuroscience, 2005Co-Authors: Zhiqiang Liu, G Raivich, Marion Bohatschek, Klaus Pfeffer, Horst BluethmannAbstract:The major histocompatibility complex (MHC) glycoproteins, MHC1 and MHC2, play a key role in the presentation of antigen and the development of the immune response. In the current study we examined the regulation of the MHC2 in the mouse brain after Facial axotomy. The normal Facial Motor Nucleus showed very few slender and elongated MHC2+ cells. Transection of the Facial nerve led to a gradual but strong upregulation in the number of MHC2+ cells, beginning at day 2 and reaching a maximum 14 days after axotomy, correlated with the induction of mRNA for tumor necrosis factor (TNF) alpha, interleukin (IL) 1beta and interferon-gamma (IFNgamma) and a peak in neuronal cell death. In almost all cases, MHC2 immunoreactivity was restricted to perivascular macrophages that colocalized with vascular basement membrane laminin and macrophage IBA1-immunoreactivity, with no immunoreactivity on phagocytic microglia, astrocytes or invading T-cells. Heterologous transplantation and systemic injection of endotoxin or IFNgamma did not affect this perivascular MHC2 immunoreactivity, and transgenic deletion of the IL1 receptor type I, or TNF receptor type 1, also had no effect. However, the deletion of IFNgamma receptor subunit 1 caused a significant increase, and that of TNF receptor type 2 a strong reduction in the number of MHC2+ macrophages, pointing to a counter-regulatory role of IFNgamma and TNFalpha in the immune surveillance of the injured nervous system.
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microglial major histocompatibility complex glycoprotein 1 in the axotomized Facial Motor Nucleus regulation and role of tumor necrosis factor receptors 1 and 2
The Journal of Comparative Neurology, 2004Co-Authors: Marion Bohatschek, Christian U A Kloss, Mariya Hristova, Klaus Pfeffer, G RaivichAbstract:Presentation of antigen is key to the development of the immune response, mediated by association of antigen with major histocompatibility complex glycoproteins abbreviated as MHC1 and MHC2. In the current study, we examined the regulation of MHC1 in the brain after Facial axotomy. The normal Facial Motor Nucleus showed no immunoreactivity for MHC1 (MHC1-IR). Transection of the Facial nerve led to a strong and selective up-regulation of MHC1-IR on the microglia in the affected Nucleus, beginning at day 2 and reaching a maximum 14 days after axotomy, coinciding with a peak influx of the T lymphocytes that express CD8, the lymphocyte coreceptor for MHC1. Specificity of the MHC1 staining was confirmed in beta2-microglobulin-deficient mice, which lack normal cell surface MHC1-IR. MHC1-IR was particularly strong on phagocytic microglia, induced by delayed neuronal cell death, and correlated with the induction of mRNA for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and interferon-gamma and the influx of T lymphocytes. Mice with severe combined immunodeficiency (scid), lacking T and B cells, showed an increase in the number of MHC1-positive nodules but no significant effect on overall MHC1-IR. Transgenic deletion of the IL1 receptor type I, or the interferon-gamma receptor type 1 subunit, did not affect the microglial MHC1-IR. However, a combined deletion of TNF receptors 1 and 2 (TNFR1&2-KO) led to a decrease in microglial MHC1-IR and to a striking absence of the phagocytic microglial nodules. Deletion of TNFR2 (p75) did not have an effect; deletion of TNFR1 (p55) reduced the diffuse microglial staining for MHC1-IR but did not abolish the MHC1(+) microglial nodules. In summary, neural injury leads to the induction of MHC1-IR on the activated, phagocytic microglia. This induction of MHC1 precedes the interaction with the immune system, at least in the Facial Motor Nucleus model. Finally, the impaired induction of these molecules, up to now, only in the TNFR-deficient mice underscores the central role of TNF in the immune activation of the injured nervous system.
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microglia and the early phase of immune surveillance in the axotomized Facial Motor Nucleus impaired microglial activation and lymphocyte recruitment but no effect on neuronal survival or axonal regeneration in macrophage colony stimulating factor deficient mice
The Journal of Comparative Neurology, 2001Co-Authors: Roger Kalla, Alexander Werner, C. U. A. Kloss, Zhiqiang Liu, Andrea Koppius, Y Imai, S Kohsaka, Andreas Gschwendtner, J C Moller, G RaivichAbstract:Activation of microglia is among the first cellular changes in the injured CNS. However, little is known about their specific contribution to secondary damage or repair processes in neighboring neurons and nonneuronal cells or to the immune surveillance of the damaged tissue. Animal models with defective microglial response such as osteopetrosis provide an approach to explore these effects. Osteopetrosis (op) is an autosomal recessive mutation with a complete deficiency of the macrophage-colony stimulating factor (MCSF; CSF-1), an important mitogen for brain microglia. In the current study we examined the effects of this MCSF deficiency on the microglial reaction and the overall cellular response to nerve injury in the mouse axotomized Facial Motor Nucleus. In the brain, MCSF receptor immunoreactivity was found only on microglia and was strongly up-regulated following injury. MCSF deficiency led to a failure of microglia to show a normal increase in early activation markers (thrombospondin, MCSF receptor, alpha M beta 2- and alpha 5 beta 1-integrins), to spread on the surface of axotomized motoneurons, and to proliferate after injury. Early recruitment of CD3(+) T-lymphocytes to the Facial Nucleus 24 hours after injury was reduced by 60%. In contrast, the neuronal and astrocyte response was not affected. There was a normal increase in the neuropeptides calcitonin gene-related peptide and galanin, neuronal c-JUN, and NADPH-diaphorase and a decrease in choline acetyltransferase and acetylcholinesterase. Astrocyte glial fibrillary acidic protein immunoreactivity also showed a normal increase. There was a normal influx of macrophages and granulocytes into the injured Facial nerve. Synaptic stripping, neuronal survival, and speed of axonal regeneration were also not affected. The current results show a strong, selective effect of MCSF on the early activation of microglia and, indirectly, on lymphocyte recruitment. This early phase of microglial activation appears not to be involved in the process of repair following peripheral nerve injury. However, it is important in the initiation of inflammatory changes in the brain and in the interaction with the immune system.
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integrin family of cell adhesion molecules in the injured brain regulation and cellular localization in the normal and regenerating mouse Facial Motor Nucleus
The Journal of Comparative Neurology, 1999Co-Authors: Christian U A Kloss, Michael A Klein, Georg W Kreutzberg, Alexander Werner, Jun Shen, Karen Menuz, Chistoph J Probst, G RaivichAbstract:Integrins are a large family of heterodimeric glycoproteins that play a crucial role in cell adhesion during development, inflammation, and tissue repair. In the current study, we investigated the localization of different integrin subunits in the mouse Facial Motor Nucleus and their regulation after transection of the Facial nerve. In the normal mouse brain, there was clear immunoreactivity for alpha5-, alpha6-, and beta1-integrin subunits on blood vessel endothelia and for alphaM- and beta2-subunits on resting parenchymal microglia. Facial nerve transection led to an up-regulation of the beta1-subunit on the axotomized neurons and an increase in the alpha4-, alpha5-, alpha6-, beta1-, alphaM-, alphaX-, and beta2-subunits on the adjacent, activated microglia. Quantification of the microglial integrins revealed two different expression patterns. The subunits alpha5 and alpha6 showed a monophasic increase with a maximum at day 4, the alphaM-subunit a biphasic regulation, with an early peak at day 1 and an elevated plateau between day 14 and 42. At day 14, there was also an influx of lymphocytes immunoreactive for the alpha4beta1- and alphaLbeta2-integrins, which aggregated at sites of neural debris and phagocytotic microglia. This finding was accompanied by a significant increase of the alpha5beta1-integrin on blood vessel endothelia. In summary, Facial axotomy is followed by a strong and cell-type-specific expression of integrins on the affected neurons and on surrounding microglia, lymphocytes, and vascular endothelia. The presence of several, strikingly different temporal patterns suggests a selective involvement of these molecules in the different adhesive events during regeneration in the central nervous system.
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immune surveillance in the injured nervous system t lymphocytes invade the axotomized mouse Facial Motor Nucleus and aggregate around sites of neuronal degeneration
The Journal of Neuroscience, 1998Co-Authors: G Raivich, Leonard L Jones, Christian U A Kloss, Alexander Werner, Harald Neumann, Georg W KreutzbergAbstract:Although the CNS is an established immune-privileged site, it is under surveillance by the immune system, particularly under pathological conditions. In the current study we examined the lymphocyte infiltration, a key component of this neuroimmune surveillance, into the axotomized Facial Motor Nucleus and analyzed the changes in proinflammatory cytokines and the blood–brain barrier. Peripheral nerve transection led to a rapid influx of CD3-, CD11a (αL, LFA1α)- and CD44-immunoreactive T-cells into the axotomized mouse Facial Motor Nucleus, with a first, low-level plateau 2–4 d after injury, and a second, much stronger increase at 14 d. These T-cells frequently formed aggregates and exhibited typical cleaved lymphocyte nuclei at the EM level. Immunohistochemical colocalization with thrombospondin (TSP), a marker for phagocytotic microglia, revealed aggregation of the T-cells around microglia removing neuronal debris. The massive influx of lymphocytes at day 14 was also accompanied by the synthesis of mRNA encoding IL1β, TNFα, and IFN-γ. There was no infiltration by the neutrophil granulocytes, and the intravenous injection of horseradish peroxidase also showed an intact blood–brain barrier. However, mice with severe combined immunodeficiency (SCID), which lack differentiated T- and B-cells, still exhibited infiltration with CD11a-positive cells. These CD11a-positive cells also aggregated around phagocytotic microglial nodules. In summary, there is a site-selective infiltration of activated T-cells into the mouse CNS during the retrograde reaction to axotomy. The striking aggregation of these lymphocytes around neuronal debris and phagocytotic microglia suggests an important role for the immune surveillance during neuronal cell death in the injured nervous system.
Virginia M Sanders - One of the best experts on this subject based on the ideXlab platform.
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cd4 t cell expression of the il 10 receptor is necessary for Facial motoneuron survival after axotomy
Journal of Neuroinflammation, 2020Co-Authors: Elizabeth M Runge, Deborah O Setter, Felicia M Kennedy, Virginia M Sanders, Abhirami K Iyer, Kathryn J JonesAbstract:After peripheral nerve transection, Facial motoneuron (FMN) survival depends on an intact CD4+ T cell population and a central source of interleukin-10 (IL-10). However, it has not been determined previously whether CD4+ T cells participate in the central neuroprotective IL-10 cascade after Facial nerve axotomy (FNA). Immunohistochemical labeling of CD4+ T cells, pontine vasculature, and central microglia was used to determine whether CD4+ T cells cross the blood-brain barrier and enter the Facial Motor Nucleus (FMNuc) after FNA. The importance of IL-10 signaling in CD4+ T cells was assessed by performing adoptive transfer of IL-10 receptor beta (IL-10RB)-deficient CD4+ T cells into immunodeficient mice prior to injury. Histology and qPCR were utilized to determine the impact of IL-10RB-deficient T cells on FMN survival and central gene expression after FNA. Flow cytometry was used to determine whether IL-10 signaling in T cells was necessary for their differentiation into neuroprotective subsets. CD4+ T cells were capable of crossing the blood-brain barrier and associating with reactive microglial nodules in the axotomized FMNuc. Full induction of central IL-10R gene expression after FNA was dependent on CD4+ T cells, regardless of their own IL-10R signaling capability. Surprisingly, CD4+ T cells lacking IL-10RB were incapable of mediating neuroprotection after axotomy and promoted increased central expression of genes associated with microglial activation, antigen presentation, T cell co-stimulation, and complement deposition. There was reduced differentiation of IL-10RB-deficient CD4+ T cells into regulatory CD4+ T cells in vitro. These findings support the interdependence of IL-10- and CD4+ T cell-mediated mechanisms of neuroprotection after axotomy. CD4+ T cells may potentiate central responsiveness to IL-10, while IL-10 signaling within CD4+ T cells is necessary for their ability to rescue axotomized motoneuron survival. We propose that loss of IL-10 signaling in CD4+ T cells promotes non-neuroprotective autoimmunity after FNA.
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impact of peripheral immune status on central molecular responses to Facial nerve axotomy
Brain Behavior and Immunity, 2018Co-Authors: Deborah O Setter, Elizabeth M Runge, Nicole D Schartz, Felicia M Kennedy, Brandon L Brown, Kathryn P Mcmillan, Whitney M Miller, Kishan M Shah, Melissa M Haulcomb, Virginia M SandersAbstract:Abstract When Facial nerve axotomy (FNA) is performed on immunodeficient recombinase activating gene-2 knockout (RAG-2−/−) mice, there is greater Facial motoneuron (FMN) death relative to wild type (WT) mice. Reconstituting RAG-2−/− mice with whole splenocytes rescues FMN survival after FNA, and CD4+ T cells specifically drive immune-mediated neuroprotection. Evidence suggests that immunodysregulation may contribute to motoneuron death in amyotrophic lateral sclerosis (ALS). Immunoreconstitution of RAG-2−/− mice with lymphocytes from the mutant superoxide dismutase (mSOD1) mouse model of ALS revealed that the mSOD1 whole splenocyte environment suppresses mSOD1 CD4+ T cell-mediated neuroprotection after FNA. The objective of the current study was to characterize the effect of CD4+ T cells on the central molecular response to FNA and then identify if mSOD1 whole splenocytes blocked these regulatory pathways. Gene expression profiles of the axotomized Facial Motor Nucleus were assessed from RAG-2−/− mice immunoreconstituted with either CD4+ T cells or whole splenocytes from WT or mSOD1 donors. The findings indicate that immunodeficient mice have suppressed glial activation after axotomy, and cell transfer of WT CD4+ T cells rescues microenvironment responses. Additionally, mSOD1 whole splenocyte recipients exhibit an increased astrocyte activation response to FNA. In RAG-2−/− + mSOD1 whole splenocyte mice, an elevation of motoneuron-specific Fas cell death pathways is also observed. Altogether, these findings suggest that mSOD1 whole splenocytes do not suppress mSOD1 CD4+ T cell regulation of the microenvironment, and instead, mSOD1 whole splenocytes may promote motoneuron death by either promoting a neurotoxic astrocyte phenotype or inducing Fas-mediated cell death pathways. This study demonstrates that peripheral immune status significantly affects central responses to nerve injury. Future studies will elucidate the mechanisms by which mSOD1 whole splenocytes promote cell death and if inhibiting this mechanism can preserve motoneuron survival in injury and disease.
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differential gene expression in the axotomized Facial Motor Nucleus of presymptomatic sod1 mice
The Journal of Comparative Neurology, 2011Co-Authors: Virginia M Sanders, Nichole A Mesnard, Kathryn J JonesAbstract:Previously, we compared molecular profiles of one population of wild-type (WT) mouse Facial motoneurons (FMNs) surviving with FMNs undergoing significant cell death after axotomy. Regardless of their ultimate fate, injured FMNs respond with a vigorous pro-survival/regenerative molecular response. In contrast, the neuropil surrounding the two different injured FMN populations contained distinct molecular differences that support a causative role for glial and/or immune-derived molecules in directing contrasting responses of the same cell types to the same injury. In the current investigation, we utilized the Facial nerve axotomy model and a presymptomatic amyotrophic lateral sclerosis (ALS) mouse (SOD1) model to experimentally mimic the axonal die-back process observed in ALS pathogenesis without the confounding variable of disease onset. Pre-symptomatic SOD1 mice had a significant decrease in FMN survival compared with WT, which suggests an increased susceptibility to axotomy. Laser microdissection was used to accurately collect uninjured and axotomized Facial Motor nuclei of WT and presymptomatic SOD1 mice for mRNA expression pattern analyses of pro-survival/pro-regeneration genes, neuropil-specific genes, and genes involved in or responsive to the interaction of FMNs and non-neuronal cells. Axotomized pre-symptomatic SOD1 FMNs displayed a dynamic pro-survival/regenerative response to axotomy, similar to WT, despite increased cell death. However, significant differences were revealed when the axotomy-induced gene expression response of presymptomatic SOD1 neuropil was compared with WT. We propose that the increased susceptibility of presymptomatic SOD1 FMNs to axotomy-induced cell death and, by extrapolation, disease progression, is not intrinsic to the motoneuron, but rather involves a dysregulated response by non-neuronal cells in the surrounding neuropil.
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effects of Facial nerve axotomy on th2 and th1 associated chemokine expression in the Facial Motor Nucleus of wild type and presymptomatic msod1 mice
Journal of Neuroimmunology, 2009Co-Authors: Derek A Wainwright, Virginia M Sanders, Nichole A Mesnard, Junping Xin, Christine M Politis, Kathryn J JonesAbstract:We have previously demonstrated a neuroprotective mechanism of Facial motoneuron (FMN) survival after Facial nerve axotomy that is dependent on CD4(+) Th2 cell interaction with peripheral antigen-presenting cells, as well as CNS resident microglia. To investigate this mechanism, we chose to study the Th2-associated chemokine, CCL11, and Th1-associated chemokine, CXCL11, in wild-type and presymptomatic mSOD1 mice after Facial nerve axotomy. In this report, the results indicate that CCL11 is constitutively expressed in the uninjured Facial Motor Nucleus, but CXCL11 is not expressed at all. Facial nerve axotomy induced a shift in CCL11 expression from FMN to astrocytes, whereas CXCL11 was induced in FMN. Differences in the number of CCL11- and CXCL11-expressing cells were observed between WT and mSOD1 mice after Facial nerve axotomy.
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effects of Facial nerve axotomy on th2 associated and th1 associated chemokine mrna expression in the Facial Motor Nucleus of wild type and presymptomatic sod1 mice
Journal of neurodegeneration & regeneration, 2009Co-Authors: Derek A Wainwright, Virginia M Sanders, Nichole A Mesnard, Junping Xin, Kathryn J JonesAbstract:The authors have previously demonstrated a neuroprotective mechanism of Facial motoneuron (FMN) survival after Facial nerve transection that is dependent on CD4(+)T helper 2 (Th2) cell interactions with peripheral antigen presenting cells, as well as central nervous system (CNS) resident microglia. Pituitary adenylyl cyclase activating polypeptide is expressed by injured FMN and increases Th2-associated chemokine expression in cultured murine microglia. Collectively, these data suggest a model involving CD4(+) Th2 cell migration to the Facial Motor Nucleus after injury via microglial expression of Th2-associated chemokines. In this study, the authors tested the hypothesis that Th2-associated chemokine expression occurs in the Facial Motor Nucleus after Facial nerve axotomy at the stylomastoid foramen. Initial microarray analysis of Th2-associated and Th1-associated chemokine mRNA levels was accomplished after Facial nerve axotomy in wild type (WT) and presymptomatic mutant superoxide dismutase 1 (mSOD1) [model of familial amyotrophic lateral sclerosis (ALS)] mice. Based on that initial microarray analysis, the Th2-associated chemokine, CCL11, and Th1-associated chemokine, CXCL11, were further analyzed by RT-PCR. The results indicate that Facial nerve injury predominantly increases Th2-associated chemokine, but not Th1-associated chemokine mRNA levels in the mouse Facial Motor Nucleus. Interestingly, no differences were detected between WT and mSOD1 mice for CCL11 and CXCL11 after injury. These data provide a basis for further investigation into Th2-associated chemokine expression in the Facial Motor Nucleus after FMN injury, which may lead to more specifically targeted therapeutics in motoneuron diseases, such as ALS.
Nichole A Mesnard - One of the best experts on this subject based on the ideXlab platform.
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differential gene expression in the axotomized Facial Motor Nucleus of presymptomatic sod1 mice
The Journal of Comparative Neurology, 2011Co-Authors: Virginia M Sanders, Nichole A Mesnard, Kathryn J JonesAbstract:Previously, we compared molecular profiles of one population of wild-type (WT) mouse Facial motoneurons (FMNs) surviving with FMNs undergoing significant cell death after axotomy. Regardless of their ultimate fate, injured FMNs respond with a vigorous pro-survival/regenerative molecular response. In contrast, the neuropil surrounding the two different injured FMN populations contained distinct molecular differences that support a causative role for glial and/or immune-derived molecules in directing contrasting responses of the same cell types to the same injury. In the current investigation, we utilized the Facial nerve axotomy model and a presymptomatic amyotrophic lateral sclerosis (ALS) mouse (SOD1) model to experimentally mimic the axonal die-back process observed in ALS pathogenesis without the confounding variable of disease onset. Pre-symptomatic SOD1 mice had a significant decrease in FMN survival compared with WT, which suggests an increased susceptibility to axotomy. Laser microdissection was used to accurately collect uninjured and axotomized Facial Motor nuclei of WT and presymptomatic SOD1 mice for mRNA expression pattern analyses of pro-survival/pro-regeneration genes, neuropil-specific genes, and genes involved in or responsive to the interaction of FMNs and non-neuronal cells. Axotomized pre-symptomatic SOD1 FMNs displayed a dynamic pro-survival/regenerative response to axotomy, similar to WT, despite increased cell death. However, significant differences were revealed when the axotomy-induced gene expression response of presymptomatic SOD1 neuropil was compared with WT. We propose that the increased susceptibility of presymptomatic SOD1 FMNs to axotomy-induced cell death and, by extrapolation, disease progression, is not intrinsic to the motoneuron, but rather involves a dysregulated response by non-neuronal cells in the surrounding neuropil.
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effects of Facial nerve axotomy on th2 and th1 associated chemokine expression in the Facial Motor Nucleus of wild type and presymptomatic msod1 mice
Journal of Neuroimmunology, 2009Co-Authors: Derek A Wainwright, Virginia M Sanders, Nichole A Mesnard, Junping Xin, Christine M Politis, Kathryn J JonesAbstract:We have previously demonstrated a neuroprotective mechanism of Facial motoneuron (FMN) survival after Facial nerve axotomy that is dependent on CD4(+) Th2 cell interaction with peripheral antigen-presenting cells, as well as CNS resident microglia. To investigate this mechanism, we chose to study the Th2-associated chemokine, CCL11, and Th1-associated chemokine, CXCL11, in wild-type and presymptomatic mSOD1 mice after Facial nerve axotomy. In this report, the results indicate that CCL11 is constitutively expressed in the uninjured Facial Motor Nucleus, but CXCL11 is not expressed at all. Facial nerve axotomy induced a shift in CCL11 expression from FMN to astrocytes, whereas CXCL11 was induced in FMN. Differences in the number of CCL11- and CXCL11-expressing cells were observed between WT and mSOD1 mice after Facial nerve axotomy.
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effects of Facial nerve axotomy on th2 associated and th1 associated chemokine mrna expression in the Facial Motor Nucleus of wild type and presymptomatic sod1 mice
Journal of neurodegeneration & regeneration, 2009Co-Authors: Derek A Wainwright, Virginia M Sanders, Nichole A Mesnard, Junping Xin, Kathryn J JonesAbstract:The authors have previously demonstrated a neuroprotective mechanism of Facial motoneuron (FMN) survival after Facial nerve transection that is dependent on CD4(+)T helper 2 (Th2) cell interactions with peripheral antigen presenting cells, as well as central nervous system (CNS) resident microglia. Pituitary adenylyl cyclase activating polypeptide is expressed by injured FMN and increases Th2-associated chemokine expression in cultured murine microglia. Collectively, these data suggest a model involving CD4(+) Th2 cell migration to the Facial Motor Nucleus after injury via microglial expression of Th2-associated chemokines. In this study, the authors tested the hypothesis that Th2-associated chemokine expression occurs in the Facial Motor Nucleus after Facial nerve axotomy at the stylomastoid foramen. Initial microarray analysis of Th2-associated and Th1-associated chemokine mRNA levels was accomplished after Facial nerve axotomy in wild type (WT) and presymptomatic mutant superoxide dismutase 1 (mSOD1) [model of familial amyotrophic lateral sclerosis (ALS)] mice. Based on that initial microarray analysis, the Th2-associated chemokine, CCL11, and Th1-associated chemokine, CXCL11, were further analyzed by RT-PCR. The results indicate that Facial nerve injury predominantly increases Th2-associated chemokine, but not Th1-associated chemokine mRNA levels in the mouse Facial Motor Nucleus. Interestingly, no differences were detected between WT and mSOD1 mice for CCL11 and CXCL11 after injury. These data provide a basis for further investigation into Th2-associated chemokine expression in the Facial Motor Nucleus after FMN injury, which may lead to more specifically targeted therapeutics in motoneuron diseases, such as ALS.
John M Petitto - One of the best experts on this subject based on the ideXlab platform.
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Reversal of Neuronal Atrophy: Role of Cellular Immunity in Neuroplasticity and Aging
2016Co-Authors: Zhi Huang, John M PetittoAbstract:Copyright: © 2014 Huang Z, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Emerging evidence indicates that neuroimmunological changes in the brain can modify intrinsic brain processes that are involved in regulating neuroplasticity. Increasing evidence suggests that in some forms of Motor neuron injury, many neurons do not die, but reside in an atrophic state for an extended period of time. In mice, Facial Motor neurons in the brain undergo a protracted period of degeneration or atrophy following resection of their peripheral axons. Reinjuring the proximal nerve stump of the chronically resected Facial nerve stimulates a robust reversal of Motor neuron atrophy which results in marked increases in both the number and size of injured Motor neurons in the Facial Motor Nucleus. In this brief review, we describe research from our lab which indicates that the reversal of atrophy in this injury model is dependent on normal cellular immunity. The role of T cells in this unique form of neuroplasticity following injury and in brain aging, are discussed. The potential role of yet undiscover intrinsic actions of recombination activating genes in the brain are considered. Further research using the Facial nerve reinjury model could identify molecular signals involved in neuroplasticity, and lead to new ways to stimulate neuroregenerative processes in neurotrauma and other forms of brain insult and disease
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t cell memory in the injured Facial Motor Nucleus relation to functional recovery following Facial nerve crush
Neuroscience Letters, 2008Co-Authors: Marlon Pastrana, Zhi Huang, John M PetittoAbstract:T cells have the ability to mount a memory response to a previously encountered antigen such that re-exposure to the antigen results in a response that is greater in magnitude and function. Following Facial nerve transection, T cells have been shown to traffic to injured Motor neurons in the Facial Motor Nucleus (FMN) and may have the ability to promote neuronal survival and functional recovery. Previously, we demonstrated that early exposure to neuronal injury on one side of the brain during young adulthood elicited a T cell response that was greater in magnitude following exposure to the same form of injury on the contralateral side later in adulthood. Whether the T cell memory response to neuronal injury influenced functional recovery following nerve crush injury was unknown. In the current study, we tested the hypotheses that (1) transection of the right Facial nerve in sensitized mice would result in faster recovery of the whisker response when the contralateral Facial nerve is crushed 10 weeks later, and (2) the early recovery would be associated with an increase in the magnitude of the T cell response in the contralateral FMN following crush injury in sensitized mice. The onset of modest recovery in sensitized mice occurred between 3 and 5 days following crush injury of the contralateral Facial nerve, approximately 1.5 days earlier than naive mice, and was associated with more than a two-fold increase in the magnitude of the T cell response in the contralateral FMN following crush injury. There was no difference between groups in the number of days to full recovery. Further study of how T cell memory influences neuroregeneration may have important implications for translational research.
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influence of injury severity on the rate and magnitude of the t lymphocyte and neuronal response to Facial nerve axotomy
Journal of Neuroimmunology, 2008Co-Authors: Shivani Parikh, Zhi Huang, John M PetittoAbstract:Abstract 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 and 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 severity of peripheral nerve injury and associated neuronal death.
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prior Facial Motor neuron injury elicits endogenous t cell memory relation to neuroregeneration
Journal of Neuroimmunology, 2007Co-Authors: Grace K Ha, Zhi Huang, John M PetittoAbstract:We tested the hypotheses that prior injury to the Facial Motor Nucleus (FMN) would elicit a more robust T cell response in the opposite FMN when the contralateral Facial nerve was injured later in life, and that this would result in improved neuroregeneration. Measures of T cell, neuronal and microglial status were compared in sensitized mice (right Facial nerve transection followed by contralateral Facial nerve transection 9.5 weeks later) and naive mice (sham surgery of the right Facial nerve followed by contralateral Facial nerve transection 9.5 weeks later) following axotomy of the contralateral Facial nerve. At day 14 post-axotomy, sensitized mice exhibited nearly a two-fold increase in T cells in the FMN compared to naive mice. There were no differences between the groups in levels of dead neurons and NeuN expression by surviving Motor neurons at day 14, or Motor neuron survival and cell area at day 49 post-axotomy. Measures of microglial responsiveness did not differ between the groups. Further study is needed to delineate the role of endogenous T cell memory in neuronal injury and regeneration.
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endogenous t lymphocytes and microglial reactivity in the axotomized Facial Motor Nucleus of mice effect of genetic background and the rag2 gene
Journal of Neuroimmunology, 2006Co-Authors: Zhi Huang, Wolfgang J Streit, John M PetittoAbstract:Following Facial nerve axotomy in mice, peripheral T cells home to the injured Facial Motor Nucleus (FMN) where they may influence the glial response. Interactions between T cells and microglia, which proliferate in response to axotomy, appear to confer neuroprotection to injured motoneurons. The primary objective of this study was to determine whether T lymphocytes could influence the microglial reaction to motoneuron injury. These experiments tested the hypotheses that (1) C57BL/6 (B6) and 129 mice, inbred strains which have high and low levels of astroglial reactivity in the axotomized FMN, respectively, would also exhibit high and low levels of T cell infiltration, and (2) that these differences would correspond with levels of microglial reactivity and neuronal regeneration. Thus, we compared the response to Facial nerve axotomy in B6, 129, and immunodeficient RAG2 knockout (RAG2 KO) mice on these two backgrounds at 14 day post-axotomy for differences in levels of 1) CD3+ T cell infiltration; (2) major histocompatibility complex II (MHC2) expression by microglia; (3) perineuronal microglial phagocytic clusters, an indirect measure of neuronal death; and (4) overall microglial activity as assessed by CD11b expression. To examine the inheritance pattern of the abovementioned neuroimmune measures, we also made assessments in B6x129 F1 generation mice. B6 and 129 mice displayed high and low levels of T cell infiltration to the affected FMN and low and high MHC2 expression, respectively. Levels of microglial activity did not differ between the two strains. In immunodeficient RAG2 KO mice on both backgrounds, the number of MHC2+ microglia did not differ from their immunologically normal background controls. Moreover, deletion of either the RAG2 or RAG1 genes in B6 mice was not associated with increased neuronal death at day 14 post-axotomy, as we had previously found in B6 mice with the severe combined immunodeficiency (SCID) mutation. Contrary to our hypothesis, the paucity of T cells in the affected FMN of the 129 mice was associated with less neuronal death when compared to B6 mice, which showed a robust T cell response. Moreover, the data suggest that parameters of the central and peripheral immune responses to axotomy are independently regulated. Assessments in B6x129 F1 generation mice revealed dominant phenotypes for both T cell infiltration and neurodegeneration, whereas both strains contributed significantly to the phenotype for MHC2 expression. Our findings suggest that (1) T cells do not appear to modify measures of microglial reactivity in the axotomized FMN; and (2) the impact of T cells on injured motoneurons in immunologically intact mice and in immunodeficient mice grafted with T cells by adoptive transfer may be different. Further study is required to understand the role of T cells following motoneuron injury in immunologically intact mice and how the seemingly divergent effects of T cells in intact and immunodeficient mice might provide insight into their role in neuronal injury and repair.
