Microglia at the Crossroads of Pathogen-Induced Neuroinflammation.

The adult mammalian central nervous system (CNS) contains a large number of different cell types, which arise from the ventricular (VZ) and subventricular zones during embryonic development. In this study, we used a transgenic mouse expressing Lmo1-LacZ from a randomly inserted promoter/reporter gene construct to identify a glial subpopulation. LMO1 is an LIM domain-containing protein, thought to act in protein-protein interactions. We found first that in the adult transgenic CNS, beta-galactosidase (beta-gal) was expressed in a specific subpopulation of protoplasmic-like cells, which did not express detectable levels of glial fibrilary acidic protein unless a lesion was produced. Secondly, during development, beta-gal(+) cells were found arising from discrete regions of the VZ. Taken together, these results identify a subpopulation of protoplasmic glial cells in the adult CNS and suggest that they arise from a restricted VZ region during CNS development.

Endoplasmic reticulum associated degradation (ERAD) is responsible for recognition and degradation of unfolded or misfolded proteins in the ER. Sel1L is essential for the ERAD activity of Sel1L-Hrd1 complex, the best-known ERAD machinery. Using a continuous Sel1L knockout mouse model (CNP/Cre; Sel1LloxP/loxP mice), our previous studies showed that Sel1L knockout in myelinating cells, oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS), leads to adult-onset myelin abnormalities in the CNS and PNS. Because Sel1L is deleted in myelinating cells of CNP/Cre; Sel1LloxP/loxP mice starting at very early stage of differentiation, it is impossible to rule out the possibility that the adult-onset myelin abnormalities in these mice results from developmental myelination defects caused by Sel1L knockout in myelinating cells during development. Thus, using an inducible Sel1L knockout mouse model (PLP/CreERT ; Sel1LloxP/loxP mice) that has normal, intact myelin and myelinating cells in the adult CNS and PNS prior to tamoxifen treatment, we sought to determine if Sel1L knockout in mature myelinating cells of adult mice leads to myelin abnormalities in the CNS and PNS. We showed that Sel1L knockout in mature myelinating cells caused ERAD impairment, ER stress and UPR activation. Interesting, Sel1L knockout in mature oligodendrocytes impaired their myelinating function by suppressing myelin protein translation, and resulted in progressive myelin thinning in the adult CNS. Conversely, Sel1L knockout in mature Schwann cells led to Schwann cell apoptosis and demyelination in the adult PNS. These findings demonstrate the essential roles of ERAD in mature myelinating cells in the adult CNS and PNS under physiological conditions.

Although oligoclonal bands in the cerebrospinal fluid have been a hallmark of multiple sclerosis diagnosis for over three decades, the role of antibody-secreting cells in multiple sclerosis remains unclear. T and B cells are critical for multiple sclerosis pathogenesis, but increasing evidence suggests that plasma cells also contribute, through secretion of autoantibodies. Long-lived plasma cells are known to drive various chronic inflammatory conditions as e.g. systemic lupus erythematosus, however, to what extent they are present in autoimmune central nervous system inflammation has not yet been investigated. In brain biopsies from multiple sclerosis patients and other neurological diseases, we could detect non-proliferating plasma cells (CD138+Ki67−) in the parenchyma. Based on this finding, we hypothesized that long-lived plasma cells can persist in the central nervous system (CNS). In order to test this hypothesis, we adapted the multiple sclerosis mouse model experimental autoimmune encephalomyelitis to generate a B cell memory response. Plasma cells were found in the meninges and the parenchyma of the inflamed spinal cord, surrounded by tissue areas resembling survival niches for these cells, characterized by an up-regulation of chemokines (CXCL12), adhesion molecules (VCAM-1) and survival factors (APRIL and BAFF). In order to determine the lifetime of plasma cells in the chronically inflamed CNS, we labeled the DNA of proliferating cells with 5-ethynyl-2′-deoxyuridine (EdU). Up to five weeks later, we could detect EdU+ long-lived plasma cells in the murine CNS. To our knowledge, this is the first study describing non-proliferating plasma cells directly in the target tissue of a chronic inflammation in humans, as well as the first evidence demonstrating the ability of plasma cells to persist in the CNS, and the ability of the chronically inflamed CNS tissue to promote this persistence. Hence, our results suggest that the CNS provides survival niches for long-lived plasma cells, similar to the niches found in other organs. Targeting these cells in the CNS offers new perspectives for treatment of chronic autoimmune neuroinflammatory diseases, especially in patients who do not respond to conventional therapies.

Expression and distribution of Toll‐like receptors in the brain during murine neurocysticercosis

BMP6 expression in the adult rat central nervous system

Adult neurogenesis, generation of new functional cells in the mature central nervous system (CNS), has been documented in a number of diverse organisms, ranging from humans to invertebrates. However, the origin and evolution of this phenomenon is still poorly understood for many of the key phylogenetic groups. Echinoderms are one such phylum, positioned as a sister group to chordates within the monophyletic clade Deuterostomia. They are well known for the ability of their adult organs, including the CNS, to completely regenerate after injury. Nothing is known, however, about production of new cells in the nervous tissue under normal physiological conditions in these animals. In this study, we show that new cells are continuously generated in the mature radial nerve cord (RNC) of the sea cucumber Holothuria glaberrima. Importantly, this neurogenic activity is not evenly distributed, but is significantly more extensive in the lateral regions of the RNC than along the midline. Some of the new cells generated in the apical region of the ectoneural neuroepithelium leave their place of origin and migrate basally to populate the neural parenchyma. Gene expression analysis showed that generation of new cells in the adult sea cucumber CNS is associated with transcriptional activity of genes known to be involved in regulation of various aspects of neurogenesis in other animals. Further analysis of one of those genes, the transcription factor Myc, showed that it is expressed, in some, but not all radial glial cells, suggesting heterogeneity of this CNS progenitor cell population in echinoderms.

IFN-γ, the hallmark cytokine of Th1 cells, plays an important role in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Thus far, the role of IFN-γ in EAE has been largely studied through its effects on immune cells, while much less is known about its effects on central nervous system (CNS) cells, especially in vivo. In this study we for the first time dissected the in vivo effects and mechanisms of IFN-γ signaling in astrocytes and microglia and found that IFN-γ signaling in these cell types has opposite effects in EAE pathogenesis. Silencing IFN-γ signaling in astrocytes ameliorated EAE, while in microglia it increased disease severity. Silencing IFN-γ signaling in astrocytes resulted in diminished expression of chemokines and fewer inflammatory cells infiltrating into the CNS, while blocking IFN-γ signaling in microglia increased disease severity through augmented activation and proliferation of microglia. Further, blocking IFN-γ signaling in astrocytes ameliorated both Th1- and Th17-mediated adoptive EAE, indicating an important role for IFN-γ signaling in astrocytes in autoimmune CNS inflammation. Thus, our study defines novel mechanisms of action of IFN-γ in EAE pathogenesis, and also highlights an opportunity for development of MS therapies directed at CNS cells.

Neural stem cells (NSCs) are an undifferentiated population of cells residing in the tissue lining the ventricular system of both the embryonic and adult mammalian central nervous system (CNS) (1–3). When isolated under the appropriate genetic or epigenetic conditions, NSCs have the ability to self renew and produce clinical amounts of cells that may be well characterized in vitro and in vivo, cryopreserved, or ready for therapeutic use. Upon transplantation into the adult CNS, NSCs integrate seamlessly within the host tissue and differentiate according to the local microenvironment into any one of the principal CNS cell types (neurons, astrocytes, or oligodendrocytes). These attributes make NSCs a good source of cells for cell replacement therapy for neurological disorders. However, this source of neural tissue will not reach the clinical stage unless it is well characterized both in vitro and in animal models.KeywordsTyrosine HydroxylaseNeural Stem CellStem Cell LineAdult Central Nervous SystemCell Replacement TherapyThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

ABSTRACTNeuroinflammation is primarily characterised by activation of the brain’s resident macrophages – the microglia. However, other central nervous system (CNS) cells also contribute to this response, including the astrocytes and endothelial cells. In addition, there is infiltration into the CNS of peripherally derived immune cells. Together these cells mediate inflammation by the production of cytokines, chemokines, reactive oxygen species, and secondary messengers, and enacting of the appropriate response to those signals. However, deciphering the specific contributions of each cell type has been challenging. Studying CNS cell biology is often challenging, as the isolation of primary cells is not always feasible, and differentiation towards microglia-like cells is complex. Here, we demonstrate a novel method whereby THP-1 monocytic cells are differentiated into neural macrophage cells with microglia-like cell characteristics. The cells, designated mgTHP-1, show typical morphological and gene expression patterns of resident CNS macrophages and functionally respond to inflammatory stimuli by producing inflammatory cytokines. Furthermore, with the addition of Vicenin-2 (an anti-inflammatory flavonoid) such responses can be reversed. This novel cell model will allow further investigations, and hence insights, into the neuroinflammatory mechanisms associated with CNS diseases.

Neuroinflammation in the central nervous system (CNS) is an important subject of neuroimmunological research. Emerging evidence suggests that neuroinflammation is a key player in various neurological disorders, including neurodegenerative diseases and CNS injury. Neuroinflammation is a complex and well-orchestrated process by various groups of glial cells in CNS and peripheral immune cells. The cross-talks between various groups of glial cells in CNS neuroinflammation is an extremely complex and dynamic process which resembles a well-orchestrated symphony. However, the understanding of how glial cells interact with each other to shape the distinctive immune responses of the CNS remains limited. In this review, we will discuss the joint actions of glial cells in three phases of neuroinflammation, including initiation, progression, and prognosis, the three movements of the symphony, as the role of each type of glial cells in neuroinflammation depends on the nature of inflammatory cues and specific course of diseases. This perspective of glial cells in neuroinflammation might provide helpful clues to the development of the early diagnosis and therapeutic intervention of the various CNS diseases.

Microtubule disruption upon CNS damage triggers mitotic entry via TNF signaling activation.

Follistatin expression in the central nervous system of the adult rat

Neuronal degeneration is a common feature of numerous neurological disorders and of aging. Following experimental or pathologic injury of the adult mammalian central nervous system (CNS), a complex cascade of events takes place that often results in severe anatomical and functional deficits Unlike neurons of the peripheral nervous system (PNS) or neurons of the developing CNS, the mature CNS displays a very limited capacity to extend axons and form appropriate connections, resulting in little constructive regeneration after damage. Studies of the developing and adult PNS have suggested that the adult CNS may be capable of achieving some degree of recovery if three critical steps are satisfied: survival or replacement of local damaged neurons, axonal growth and extension, and appropriate target innervation and functional recovery.

ing new nerve and glial cells throughout life, is a phylogenetically highly conserved feature that challenges the dogma of the nervous system as a static, non-renewable tissue (Gage, 2000). Yet, unlike invertebrates and non-mammalian vertebrates, in which neurogenesis persists in wide regions of the central nervous system (CNS), in adult mammals it is mainly restricted to two specific brain sites: the forebrain subventricular zone and the hippocampal dentate gyrus (Gage, 2000; Kriegstein and AlvarezBuylla, 2009). It is now clear that the persistence of neurogenesis in these zones depends on stem cells which reside in niches as vestigial remnants of embryonic germinal layers (Kriegstein and AlvarezBuylla, 2009). This fact leaves the remainder of the CNS as a non-renewable tissue substantially incapable to repair damage coming from neurodegenerative diseases, ischemic/traumatic lesions. In the last few years, the persistence of neurogenesis has been observed also in other CNS sites and in sensory organs, in addition to the neurogenic zones quoted above. The most striking example, known for many years, is that of olfactory receptor neurons which are continuously renewed in the olfactory mucosa (see article by Mackay-Sim, in this issue). Other examples have subsequently emerged and this special issue deals specifically with these less studied stem/progenitor cells responsible for adult neurogenesis in niches outside the forebrain and hippocampus. The review by Locker et al. summarizes a decade of research on quiescent stem cells in the mammalian retina, also taking into account the advances made in animal models of stem cell-mediated retinal regeneration. The article by Metzger gives an overview of the development, structure and function of the enteric nervous system, focusing on the persistence of neural stem cells in the gut. Pardal et al. report on stem cells existing in the carotid body, a chemoreceptor organ of the peripheral nervous system that supports neurogenesis in response to hypoxemia. Finally, Miura and Barlow address the issue of the continuous renewal of taste receptor cells, a type of electrochemically excitable cells which are epithelial in origin but capable of releasing neurotransmitter onto afferent nerve fibers. Proliferating/quiescent progenitor cells have been demonstrated to occur even in diverse regions of the adult CNS out of the forebrain and hippocampus (Nishiyama et al., 2009; Ohira et al., 2009). These additional neurogenic sites also raise the issue of comparative studies in mammalian species and in other animal groups. The occurrence of neurogenesis within the mature brain parenchyma, not related with persistent germinal layers, can be frequently found in non-vertebrate species which harbour disperse, highly active niche-like neurogenic sites in widespread CNS regions (Kaslin et al., 2008) accounting for remarkable regenerative capacity (Zupanc, 2009). By contrast, most local Exploring neurogenesis outside the niche: atypical locations of mammalian neural stem/progenitor cells

Studies of regeneration of transected adult central nervous system (CNS) axons are difficult due to lack of appropriate in vivo models. In adult rats, we described filum terminale (FT), a caudal slender extension of the sacral spinal cord and an integral part of the central nervous system (CNS), to use it as a model of spinal cord injury. FT is more than 3 cm long, encompasses a central canal lined with ependymal cells surrounded by a narrow band of axons interspersed with oligodendrocytes and astrocytes but not neurons. Two weeks after the crush of FT, histological, ultrastructural, and axonal tracing studies revealed long distance descending axonal regeneration uniquely in close proximity of the ependymal cells of the central canal. Ependymal cells extended basal processes to form channels encompassing axons apparently regenerating at a rate of more than 2 mm a day. Remarkable increase of axonal sprouting was observed in the sacral spinal cord of Long Evans Shaker (LES) rats with crushed FT. FT offers an excellent model to study mechanisms of axonal regeneration regulated by ependymal cells in the adult CNS.