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2.
J Clin Invest ; 125(2): 699-714, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25607842

RESUMO

A body of experimental evidence suggests that T cells mediate neuroprotection following CNS injury; however, the antigen specificity of these T cells and how they mediate neuroprotection are unknown. Here, we have provided evidence that T cell-mediated neuroprotection after CNS injury can occur independently of major histocompatibility class II (MHCII) signaling to T cell receptors (TCRs). Using two murine models of CNS injury, we determined that damage-associated molecular mediators that originate from injured CNS tissue induce a population of neuroprotective, IL-4-producing T cells in an antigen-independent fashion. Compared with wild-type mice, IL-4-deficient animals had decreased functional recovery following CNS injury; however, transfer of CD4+ T cells from wild-type mice, but not from IL-4-deficient mice, enhanced neuronal survival. Using a culture-based system, we determined that T cell-derived IL-4 protects and induces recovery of injured neurons by activation of neuronal IL-4 receptors, which potentiated neurotrophin signaling via the AKT and MAPK pathways. Together, these findings demonstrate that damage-associated molecules from the injured CNS induce a neuroprotective T cell response that is independent of MHCII/TCR interactions and is MyD88 dependent. Moreover, our results indicate that IL-4 mediates neuroprotection and recovery of the injured CNS and suggest that strategies to enhance IL-4-producing CD4+ T cells have potential to attenuate axonal damage in the course of CNS injury in trauma, inflammation, or neurodegeneration.


Assuntos
Axônios/imunologia , Lesões Encefálicas/imunologia , Linfócitos T CD4-Positivos/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Interleucina-4/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Doenças Neurodegenerativas/imunologia , Animais , Axônios/patologia , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Linfócitos T CD4-Positivos/patologia , MAP Quinases Reguladas por Sinal Extracelular/genética , MAP Quinases Reguladas por Sinal Extracelular/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Interleucina-4/genética , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/imunologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia
3.
J Neurochem ; 125(3): 399-409, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23418755

RESUMO

The testicans are a three-member family of secreted proteoglycans structurally related to the BM-40/secreted protein acidic and rich in cystein (SPARC) osteonectin family of extracellular calcium-binding proteins. In vitro studies have indicated that testicans are involved in the regulation of extracellular protease cascades and in neuronal function. Here, we describe the biochemical characterization and tissue distribution of mouse testican-3 as well as the inactivation of the corresponding gene. The expression of testican-3 in adult mice is restricted to the brain, where it is located diffusely within the extracellular matrix, as well as associated with cells. Brain-derived testican-3 is a heparan sulphate proteoglycan. In cell culture, the core protein is detected in the supernatant and the extracellular matrix, whereas the proteoglycan form is restricted to the supernatant. This indicates possible interactions of the testican-3 core protein with components of the extracellular matrix which are blocked by addition of the glycosaminoglycan chains. Mice deficient in testican-3 are viable and fertile and do not show an obvious phenotype. This points to a functional redundancy among the different members of the testican family or between testican-3 and other brain heparan sulphate proteoglycans.


Assuntos
Osteonectina/metabolismo , Proteoglicanas/genética , Proteoglicanas/metabolismo , Sequência de Aminoácidos , Animais , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Linhagem Celular Tumoral , Clonagem Molecular , Matriz Extracelular/metabolismo , Fibrossarcoma/patologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Imunoprecipitação , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteoglicanas/deficiência , Transfecção
4.
J Neuroinflammation ; 8: 183, 2011 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-22200088

RESUMO

Pro-inflammatory cytokines such as interleukin-1 beta (IL-1ß) are considered to exert detrimental effects during brain trauma and in neurodegenerative disorders. Consistently, it has been demonstrated that IL-1ß suppresses neurotrophin-mediated neuronal cell survival rendering neurons vulnerable to degeneration. Since neurotrophins are also well known to strongly influence axonal plasticity, we investigated here whether IL-1ß has a similar negative impact on neurite growth. We analyzed neurite density and length of organotypic brain and spinal cord slice cultures under the influence of the neurotrophins NGF, BDNF, NT-3 and NT-4. In brain slices, only NT-3 significantly promoted neurite density and length. Surprisingly, a similar increase of neurite growth was induced by IL-1ß. Additionally, both factors increased the number of brain slices displaying maximal neurite growth. Furthermore, the co-administration of IL-1ß and NT-3 significantly increased the number of brain slices displaying maximal neurite growth compared to single treatments. These data indicate that these two factors synergistically stimulate two distinct aspects of neurite outgrowth, namely neurite density and neurite length from acute organotypic brain slices.


Assuntos
Encéfalo/efeitos dos fármacos , Interleucina-1beta/metabolismo , Neuritos/efeitos dos fármacos , Neurotrofina 3/metabolismo , Medula Espinal/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Crescimento Neural/metabolismo , Fator de Crescimento Neural/farmacologia , Plasticidade Neuronal/fisiologia , Neurotrofina 3/farmacologia , Técnicas de Cultura de Órgãos , Medula Espinal/metabolismo
5.
Exp Brain Res ; 205(2): 215-21, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20640412

RESUMO

In this study, we investigated the hypothesis whether neurotrophins have a differential influence on neurite growth from the entorhinal cortex depending on the presence or absence of hippocampal target tissue. We investigated organotypic brain slices derived from the entorhinal-hippocampal system to analyze the effects of endogenous and recombinant neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) on neurite outgrowth and reinnervation. In the reinnervation assay, entorhinal cortex explants of transgenic mice expressing enhanced green fluorescent protein (EGFP) were co-cultured with wild-type hippocampi under the influence of recombinant NT-3 and NT-4 (500 ng/ml). Both recombinant NT-3 and NT-4 significantly increased the growth of EGFP+ nerve fibers into the target tissue. Consistently, reinnervation of the hippocampi of NT-4(-/-) and NT-3(+/-)NT-4(-/-) mice was substantially reduced. In contrast, the outgrowth assay did not exhibit reduction in axon outgrowth of NT-4(-/-) or NT-3(+/-)NT-4(-/-) cortex explants, while the application of recombinant NT-3 (500 ng/ml) induced a significant increase in the neurite extension of cortex explants. Recombinant NT-4 had no effect. In summary, only recombinant NT-3 stimulates axon outgrowth from cortex explants, while both endogenous and recombinant NT-3 and NT-4 synergistically promote reinnervation of the denervated hippocampus. These results suggest that endogenous and exogenous NT-3 and NT-4 differentially influence neurite growth depending on the presence or absence of target tissue.


Assuntos
Axônios/fisiologia , Hipocampo/fisiologia , Fatores de Crescimento Neural/fisiologia , Regeneração Nervosa/fisiologia , Neurotrofina 3/fisiologia , Animais , Axônios/efeitos dos fármacos , Carbazóis/farmacologia , Córtex Entorrinal/citologia , Córtex Entorrinal/crescimento & desenvolvimento , Córtex Entorrinal/fisiologia , Inibidores Enzimáticos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Alcaloides Indólicos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/farmacologia , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/genética , Neurônios/fisiologia , Neurotrofina 3/genética , Neurotrofina 3/farmacologia , Receptores de Fator de Crescimento Neural/antagonistas & inibidores , Proteínas Recombinantes/farmacologia
6.
Brain Pathol ; 20(4): 771-9, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20070303

RESUMO

Systemic or brain-selective hypothermia is a well-established method for neuroprotection after brain trauma. There is increasing evidence that hypothermia exerts beneficial effects on the brain and may also support regenerative responses after brain damage. Here, we have investigated whether hypothermia influences neurite outgrowth in vitro via modulation of the post-injury cytokine milieu. Organotypic brain slices were incubated: deep hypothermia (2 h at 17 degrees C), rewarming (2 h up to 37 degrees C), normothermia (20 h at 37 degrees C). Neurite density and cytokine release (IL 1beta, IL-6, IL-10, and TNF-alpha) were investigated after 24 h. For functional analysis mice deficient in NT-3/NT-4 and TNF-alpha as well as the TNF-alpha inhibitor etanercept were used. Hypothermia led to a significant increase of neurite outgrowth, which was independent of neurotrophin signaling. In contrast to other cytokines investigated, TNF-alpha secretion by organotypic brain slices was significantly increased after deep hypothermia. Moreover, hypothermia-induced neurite extension was abolished after administration of the TNF-alpha inhibitor and in TNF-alpha knockout mice. We demonstrate that TNF-alpha is responsible for inducing neurite outgrowth in the context of deep hypothermia and rewarming. These data suggest that hypothermia not only exerts protective effects in the CNS but may also support neurite outgrowth as a potential mechanism of regeneration.


Assuntos
Temperatura Baixa , Córtex Entorrinal/metabolismo , Neuritos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Córtex Entorrinal/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Etanercepte , Imunoglobulina G/farmacologia , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Fatores de Crescimento Neural/metabolismo , Neuritos/efeitos dos fármacos , Neurotrofina 3/metabolismo , Técnicas de Cultura de Órgãos , Receptores do Fator de Necrose Tumoral , Reaquecimento , Estatísticas não Paramétricas , Fator de Necrose Tumoral alfa/antagonistas & inibidores
7.
Brain Res Rev ; 52(1): 160-9, 2006 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-16497382

RESUMO

The culture of hippocampal-entorhinal brain slices is a widely used model for studying neuronal differentiation, axon growth and pathfinding in vitro. The application of tracers (e.g. biocytin) is a well-established method for studying single or multiple neurons and their extensions in this model. For quantifying the growth of high numbers of axons after lesion, however, genetically expressed enhanced green fluorescent protein (EGFP) has proven particularly useful for labeling living axons in vivo and in vitro. Here, we introduce several EGFP-expressing mouse lines which improve the organotypic brain slice model. The questions addressed determine which mouse line to use: beta-actin-EGFP mice for labeling all cells and their extensions; Tau-EGFP mice for labeling the axoplasma; or Thy-1.2-EGFP mice for labeling the axonal membrane. Cocultures of EGFP-positive entorhinal cortex explants with EGFP-negative hippocampal explants allow the monitoring of fluorescent axons growing into the hippocampus in an easily quantifiable manner.


Assuntos
Axônios/fisiologia , Proteínas de Fluorescência Verde/metabolismo , Modelos Animais , Regeneração Nervosa/fisiologia , Animais , Expressão Gênica/fisiologia , Proteínas de Fluorescência Verde/genética , Humanos , Técnicas In Vitro , Camundongos
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