Brain inflammation, a common feature in neurodegenerative diseases, is a complex series of events, which can be detrimental and even lead to neuronal death. Nonetheless, several studies suggest that inflammatory signals are also positively influencing neural cell proliferation, survival, migration, and differentiation. Recently, correlative studies suggested that astrocytes are able to dedifferentiate upon injury and may thereby re-acquire neural stem cell (NSC) potential. However, the mechanism underlying this dedifferentiation process upon injury remains unclear. Here, we report that during the early response of reactive gliosis, inflammation induces a conversion of mature astrocytes into neural progenitors. A TNF treatment induces the decrease of specific astrocyte markers, such as glial fibrillary acidic protein (GFAP) or genes related to glycogen metabolism, while a subset of these cells re-expresses immaturity markers, such as CD44, Musashi-1, and Oct4. Thus, TNF treatment results in the appearance of cells that exhibit a neural progenitor phenotype and are able to proliferate and differentiate into neurons and/or astrocytes. This dedifferentiation process is maintained as long as TNF is present in the culture medium. In addition, we highlight a role for Oct4 in this process, since the TNF-induced dedifferentiation can be prevented by inhibiting Oct4 expression. Our results show that activation of the NF-κB pathway through TNF plays an important role in the dedifferentiation of astrocytes via the re-expression of Oct4. These findings indicate that the first step of reactive gliosis is in fact a dedifferentiation process of resident astrocytes mediated by the NF-κB pathway.Electronic supplementary materialThe online version of this article (doi:10.1007/s12035-015-9428-3) contains supplementary material, which is available to authorized users.
In this study, we examined where immune cells and nerve fibres are located in mouse Peyer's patches, with a view to identifying potential sites for neuroinvasion by prions. Special attention was paid to dendritic cells, viewed as candidate transporters of infectious prion. Double immunofluorescence labellings with anti-CD11c antibody and marker for other immune cells (B cells, T cells, follicular dendritic cells) were carried out and analysed by confocal microscopy on Peyer's patch cryosections. To reveal the extensive ganglionated networks of the myenteric and submucosal plexi and the sparse meshworks of nerve strands, we used antibodies directed against different neurofilament subunits or against glial fibrillary acidic protein. In the suprafollicular dome, dendritic cells connect, via their cytoplasmic extensions, enterocytes with M cells of the follicle-associated epithelium. They are also close to B and T cells. Nerve fibres are detected in the suprafollicular dome, notably in contact with dendritic cells. Similar connections between dendritic cells, T cells, and nerve fibres are seen in the interfollicular region. Germinal centres are not innervated; inside them dendritic cells establish contacts with follicular dendritic cells and with B cells. After immunolabelling of normal prion protein, dendritic cells of the suprafollicular dome are intensely positive labelled.
Alzheimer's disease (AD) is characterized by the presence of extracellular deposits referred to beta-amyloid (Ab) complexes or senile plaques. Ab peptide is firstly produced as monomers, readily aggregating to form multimeric complexes, of which the smallest aggregates are known to be the most neurotoxic. In AD patients, abundant reactive microglia migrate to and surround the Ab plaques. Though it is well known that microglia are activated by Ab, little is known about the peptide conformation and the signaling cascades responsible for this activation. In this study, we have stimulated murine microglia with different Ab(1-42) forms, inducing an inflammatory state, which was peptide conformation-dependent. The lightest oligomeric forms induced a more violent inflammatory response, whereas the heaviest oligomers and the fibrillar conformation were less potent inducers. BocMLF, a formylpeptide chemotactic receptor 2 antagonist, decreased the oligomeric Ab-induced inflammatory response. The Ab-induced signal transduction was found to depend on phosphorylation mechanisms mediated by MAPKs and on activator protein 1/nuclear factor kappa-light-chain-enhancer of activated B cells pathways activation. These results suggest that the reactive microgliosis intensity during AD might depend on the disease progression and consequently on the Ab conformation production. The recognition of Ab by the formylpeptide chemotactic receptor 2 seems to be a starting point of the signaling cascade inducing an inflammatory state.
Objective: The thymus is the primary lymphoid organ responsible for T cell development and the establishment of central self-tolerance. Among thymic epithelial cells, thymic nurse cells (TNC) interact closely with immature thymocytes and constitute a special microenvironment for T cell differentiation and selection. In addition, TNC express neuroendocrine self-antigens such as oxytocin and insulin-like growth factor-2, whose intrathymic transcription is regulated by the autoimmune regulator gene/protein (Aire). Both effector and natural regulatory T cell (nTreg) lineages develop in the thymus, but the mechanisms leading to nTreg selection in the thymus are still unclear. Foxp3 is the most specific nTreg marker that is required for nTreg functional activity, but not for engagement into the Treg lineage. Aire has been suggested to be a potential factor implicated in this role. The objective of this study was to characterize Aire and Foxp3 expression in TNC/thymocyte complexes. Methods:Aire and Foxp3 expression was investigated by RT-qPCR in TNC/thymocyte complexes isolated by enzymatic digestion and sedimentation. Aire and Foxp3 proteins were located by confocal microscopy and specific immunocytochemistry. Results: Both Aire and Foxp3 transcripts were detected in TNC/thymocyte complexes. Foxp3 was detected in the nucleus of thymocytes internalized into TNC. Aire was located mainly in TNC cytoplasm and, although to a lower degree, in the nucleus of some TNC-associated thymocytes. Conclusions: Aire and Foxp3 are present in the particular TNC microenvironment which has previously been shown to support thymic selection. The differential localization of these two markers suggests a role for TNC in nTreg development.
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