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1.
The balance between cathepsin C and cystatin F controls remyelination in the brain of Plp1‐overexpressing mouse,a chronic demyelinating disease model
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Jiayi Li Manabu Abe Kenji Sakimura Banthit Chetsawang Yoshinori Sahara Koujiro Tohyama Kenji F. Tanaka Kazuhiro Ikenaka 《Glia》2017,65(6):917-930
In demyelinating diseases such as multiple sclerosis (MS), an imbalance between the demyelination and remyelination rates underlies the degenerative processes. Microglial activation is observed in demyelinating lesions; however, the molecular mechanism responsible for the homeostatic/environmental change remains elusive. We previously found that cystatin F (CysF), a cysteine protease inhibitor, is selectively expressed in microglia only in actively demyelinating/remyelinating lesions but ceases expression in chronic lesions, suggesting its role in remyelination. Here, we report the effects of manipulating the expression of CysF and cathepsin C (CatC), a key target of CysF, in a murine model of transgenic demyelinating disease, Plp4e/‐. During the active remyelinating phase, both CysF knockdown (CysFKD) and microglial‐selective CatC overexpression (CatCOE) showed a worsening of the demyelination in Plp4e/‐ transgenic mice. Conversely, during the chronic demyelinating phase, CatC knockdown (CatCKD) ameliorated the demyelination. Our results suggest that the balance between CatC and CysF expression controls the demyelination and remyelination process. 相似文献
2.
Yu Zhu Hans-Gustaf Ljunggren Eilhard Mix Hu-Lun Li Peter van der Meide Adlan M. Elhassan Bengt Winblad Jie Zhu 《Experimental neurology》2001,169(2):472
Experimental autoimmune neuritis (EAN) is an animal model of the human disease Guillain–Barré syndrome. In this autoimmune inflammatory disease, CD4+ T cells mediate demyelination in the peripheral nervous system (PNS). Infiltrating macrophages and T cells as well as cytokines like interferon (IFN)-γ are intimately involved in causing pathogenic effects. To investigate the role of IFN-γ in cell-mediated EAN, IFN-γ receptor-deficient mutant (IFN-γR−/−) C57BL/6 mice and corresponding wild-type mice were immunized with P0 peptide 180–199, a purified component of peripheral nerve myelin, and Freund's complete adjuvant. IFN-γR−/− mice exhibited later onset of clinical disease. The disease was also less severe than in wild-type mice. Fewer IL-12-producing but more IL-4-producing cells were found in sciatic nerve sections from IFN-γR−/− mice than from wild-type mice on day 24 postimmunization, i.e., at the peak of clinical EAN. At the same time, IFN-γR−/− mice had less infiltration of inflammatory cells, including macrophages, CD4+ T cells, and monocytes, into sciatic nerve tissue and less demyelination. However, numbers of IFN-γ-secreting cells from the spleen were significantly augmented in the IFN-γR−/− mice, reflecting a failure of negative feedback circuits. The IFN-γR deficiency did not affect the production of anti-P0 peptide 180–199-specific antibodies. These results indicate that IFN-γ contributes to a susceptibility for EAN in C57BL/6 mice by promoting a Th1 cell-mediated immune response and suppressing a Th2 response. 相似文献
3.
Adam Elhofy R. William DePaolo Sergio A. Lira Nicholas W. Lukacs William J. Karpus 《Journal of neuroimmunology》2009,213(1-2):91-99
Chemokines are a superfamily of chemotactic cytokines that play an important role in leukocyte trafficking and have been implicated as functional mediators of immunopathology in experimental autoimmune encephalomyelitis (EAE). In the present study, we investigated the role of the CCL20 receptor, CCR6, in chronic EAE. After immunization with myelin oligodendrocyte glycoprotein 35–55 in CFA, CCR6−/− mice developed a significantly more severe chronic EAE as compared to wild type immunized animals. CCR6 expression was not required by T cells to induce EAE. Measurement of peripheral T cell responses showed differences in IFN-γ and IL-17 responses between CCR6−/− and wild type mice. At the time when CCR6−/− mice showed significantly more severe chronic EAE there was a significant decrease in PD-L1-expressing mDC in the spleens and no differences in Foxp3 Treg. Furthermore, add back of mDC with increased PD-L1 expression to CCR6−/− mice reduced the severe chronic EAE disease phase to that of wild type controls. The results suggest a role for CCR6-expressing PDL1+ mDC in regulating EAE progression. 相似文献
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Intracerebral infection of susceptible SJL/J (H-2s) mice with the Daniel’s strain of Theiler’s murine encephalomyelitis virus produces chronic, progressive, inflammatory central
nervous system demyelination, with minimal spontaneous remyelination. To assess the role of host genetic factors in spontaneous
myelin repair following chronic infection with the Daniel’s strain of Theiler’s virus, we examined demyelination and spontaneous
remyelination in strain A mice after infection with Theiler’s virus. We found that A.BY/SnJ (H-2b) mice were resistant to Theiler’s virus-induced demyelination, whereas A/J (H-2a), A/WySnJ (H-2a), and A.SW/SnJ (H-2s) mice all developed chronic demyelination with substantial spontaneous remyelination 90 days after infection. In the spinal
cords of both A/J and A/WySnJ mice, one quarter of the total lesion area showed spontaneous remyelination, whereas in A.SW/SnJ
mice, the extent of remyelination increased to two thirds of the total lesion area. The spontaneous remyelination seen in
strain A mice was consistent with myelin repair by oligodendrocytes and Schwann cells, and occurred despite the presence of
persistent virus antigen. These results indicate that host-pathogen interactions play an important role in myelin regeneration
after virus-induced demyelination, and suggest that host genetic factors influence spontaneous remyelination.
Received: 3 October 1995 / Revised, accepted: 28 November 1995 相似文献
6.
Neurotrophin 3 (NT-3) is an important autocrine factor supporting Schwann cell (SC) survival and differentiation in the absence of axons. Prior studies have failed to define the explicit role of SC versus axon in NT-3 deficiency in relation to nerve regeneration and associated remyelination. In the paradigm we studied, using NT-3 heterozygous (NT3+/−) knockout mice capable of survival into adult-life, the experimental design provided a model uniquely capable of differentiating SC/axon influences. In these studies we first identified a defect in nerve regeneration characterized by fewer SCs in the regenerating nerve fibers of crushed sciatic nerves of NT3+/− mice. Subsequent experiments differentiated SC versus axonal influences as the culprit in defective nerve regeneration using sciatic nerve transplant paradigms. Results show an impairment in nerve regeneration in NT3+/− mice with a retardation of the myelination process, and this defect is associated with decreased SC survival and an increase in the neurofilament packing density of regenerating axons. These observations indicate that NT3+/− status of the SCs, but not of the axons, is responsible for impaired nerve regeneration and that NT-3 is essential for SC survival in early stages of regeneration-associated myelination in the adult peripheral nerve. 相似文献
7.
Anthony Lyons Keith McQuillan Brian F. Deighan Julie-Ann OReilly Eric J. Downer Aine C. Murphy Melanie Watson Alessia Piazza Florence OConnell Rebecca Griffin Kingston H.G. Mills Marina A. Lynch 《Brain, behavior, and immunity》2009,23(7):1020-1027
Maintenance of the balance between pro- and anti-inflammatory cytokines in the brain, which is affected by the activation state of microglia, is important for maintenance of neuronal function. Evidence has suggested that IL-4 plays an important neuromodulatory role and has the ability to decrease lipopolysaccharide-induced microglial activation and the production of IL-1β. We have also demonstrated that CD200–CD200R interaction is involved in immune homeostasis in the brain. Here, we investigated the anti-inflammatory role of IL-4 and, using in vitro and in vivo analysis, established that the effect of lipopolysaccharide was more profound in IL-4−/−, compared with wildtype, mice. Intraperitoneal injection of lipopolysaccharide exerted a greater inhibitory effect on exploratory behaviour in IL-4−/−, compared with wildtype, mice and this was associated with evidence of microglial activation. We demonstrate that the increase in microglial activation is inversely related to CD200 expression. Furthermore, CD200 was decreased in neurons prepared from IL-4−/− mice, whereas stimulation with IL-4 enhanced CD200 expression. Importantly, neurons prepared from wildtype, but not from IL-4−/−, mice attenuated the lipopolysaccharide-induced increase in pro-inflammatory cytokine production by glia. These findings suggest that the neuromodulatory effect of IL-4, and in particular its capacity to maintain microglia in a quiescent state, may result from its ability to upregulate CD200 expression on neurons. 相似文献
8.
In the present work we analyzed the capacity of thyroid hormones (THs) to improve remyelination using a rat model of cuprizone-induced demyelination previously described in our laboratories. Twenty one days old Wistar rats were fed a diet containing 0.6% cuprizone for two weeks to induce demyelination. After cuprizone withdrawal, rats were injected with triiodothyronine (T3). Histological studies carried out in these animals revealed that remyelination in the corpus callosum (CC) of T3-treated rats improved markedly when compared to saline treated animals. The cellular events occurring in the CC and in the subventricular zone (SVZ) during the first week of remyelination were analyzed using specific oligodendroglial cell (OLGc) markers. In the CC of saline treated demyelinated animals, mature OLGcs decreased and oligodendroglial precursor cells (OPCs) increased after one week of spontaneous remyelination. Furthermore, the SVZ of these animals showed an increase in early progenitor cell numbers, dispersion of OPCs and inhibition of Olig and Shh expression compared to non-demyelinated animals. The changes triggered by demyelination were reverted after T3 administration, suggesting that THs could be regulating the emergence of remyelinating oligodendrocytes from the pool of proliferating cells residing in the SVZ. Our results also suggest that THs receptor β mediates T3 effects on remyelination. These results support a potential role for THs in the remyelination process that could be used to develop new therapeutic approaches for demyelinating diseases. 相似文献
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N. M. Moll E. Hong M. Fauveau M. Naruse C. Kerninon V. Tepavcevic A. Klopstein D. Seilhean L.‐J. Chew V. Gallo B. Nait Oumesmar 《Glia》2013,61(10):1659-1672
We have previously demonstrated that Sox17 expression is prominent at developmental stages corresponding to oligodendrocyte progenitor cell (OPC) cycle exit and onset of differentiation, and that Sox17 promotes initiation of OPC differentiation. In this study, we examined Sox17 expression and regulation under pathological conditions, particularly in two animal models of demyelination/remyelination and in post‐mortem multiple sclerosis (MS) brain lesions. We found that the number of Sox17 expressing cells was significantly increased in lysolecithin (LPC)‐induced lesions of the mouse spinal cord between 7 and 30 days post‐injection, as compared with controls. Sox17 immunoreactivity was predominantly detected in Olig2+ and CC1+ oligodendrocytes and rarely in NG2+ OPCs. The highest density of Sox17+ oligodendrocytes was observed at 2 weeks after LPC injection, coinciding with OPC differentiation. Consistent with these findings, in cuprizone‐treated mice, Sox17 expression was highest in newly generated and in maturing CC1+ oligodendrocytes, but low in NG2+ OPCs during the demyelination and remyelination phases. In MS tissue, Sox17 was primarily detected in actively demyelinating lesions and periplaque white matter. Sox17 immunoreactivity was co‐localized with NOGO‐A+ post‐mitotic oligodendrocytes both in active MS lesions and periplaque white matter. Taken together, our data: (i) demonstrate that Sox17 expression is highest in newly generated oligodendrocytes under pathological conditions and could be used as a marker of oligodendrocyte regeneration, and (ii) are suggestive of Sox17 playing a critical role in oligodendrocyte differentiation and lesion repair. GLIA 2013;61:1659–1672 相似文献
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Wung JK Perry G Kowalski A Harris PL Bishop GM Trivedi MA Johnson SC Smith MA Denhardt DT Atwood CS 《Current Alzheimer research》2007,4(1):67-72
Osteopontin (OPN) is a glycophosphoprotein expressed by several cell types and has pro-adhesive, chemotactic, and cytokine-like properties. OPN is involved in a number of physiologic and pathologic events including angiogenesis, apoptosis, inflammation, oxidative stress, remyelination, wound healing, bone remodeling, cell migration and tumorigenesis. Since these functions of OPN, and the events that it regulates, are involved with neurodegeneration, we examined whether OPN was differentially expressed in the hippocampus of the Alzheimer's disease (AD) compared with age-matched (59-93 years) control brain. We report for the first time the immunocytochemical localization of OPN in the cytoplasm of pyramidal neurons. In AD brains, there was a significant 41 % increase in the expression of neuron OPN compared with age-matched control brain. No staining of other neuronal cell types was observed. Additionally, there was a significant positive correlation between OPN staining intensity and both amyloid-beta load (r(2) = 0.25; P < 0.05; n = 20) and aging (r(2) = 0.32; P < 0.01; n = 20) among all control and AD subjects. Controlling for age indicated that OPN expression was significantly influenced by amyloid-beta load, but not age. While the functional consequences of this amyloid-beta associated increase in OPN expression are unclear, it is notable that OPN is primarily localized to those neurons that are known to be vulnerable to AD-related neurite loss, degeneration and death. Given that the induction of OPN expression (and amyloid-beta generation) is associated with remodeling and tumorigenesis, our results suggest that OPN may play a role in the aberrant re-entry of neurons into the cell cycle and/or neuronal remyelination in AD. 相似文献
13.
Enrique Garea Rodriguez Christiane Wegner Mario Kreutzfeldt Katharina Neid Dietmar R. Thal Tanja Jürgens Wolfgang Brück Christine Stadelmann Doron Merkler 《Acta neuropathologica》2014,128(2):231-246
Cerebral cortex shows a high endogenous propensity for remyelination. Yet, widespread subpial cortical demyelination (SCD) is a common feature in progressive multiple sclerosis (MS) and can already be found in early MS. In the present study, we compared oligodendroglial loss in SCD in early and chronic MS. Furthermore, we addressed in an experimental model whether repeated episodes of inflammatory SCD could alter oligodendroglial repopulation and subsequently lead to persistently demyelinated cortical lesions. NogoA+ mature oligodendrocytes and Olig2+ oligodendrocyte precursor cells were examined in SCD in patients with early and chronic MS, normal-appearing MS cortex, and control cortex as well as in the rat model of repeated targeted cortical experimental autoimmune encephalomyelitis (EAE). NogoA+ and Olig2+ cells were significantly reduced in SCD in patients with chronic, but not early MS. Repeated induction of SCD in rats resulted only in a transient loss of NogoA+, but not Olig2+ cells during the demyelination phase. This phase was followed by complete oligodendroglial repopulation and remyelination, even after four episodes of demyelination. Our data indicate efficient oligodendroglial repopulation in subpial cortical lesions in rats after repeated SCD that was similar to early, but not chronic MS cases. Accordingly, four cycles of experimental de- and remyelination were not sufficient to induce sustained remyelination failure as found in chronic cortical MS lesions. This suggests that alternative mechanisms contribute to oligodendrocyte depletion in chronic cortical demyelination in MS. 相似文献
14.
The adult mammalian brain contains multiple populations of endogenous progenitor cell types. However, following CNS trauma or disease, the regenerative capacity of progenitor populations is typically insufficient and may actually be limited by non-permissive or inhibitory signals in the damaged parenchyma. Remyelination is the most effective and simplest regenerative process in the adult CNS yet is still insufficient following repeated or chronic demyelination. Our previous in vitro studies demonstrated that fibroblast growth factor receptor 1 (FGFR1) signaling inhibited oligodendrocyte progenitor (OP) differentiation into mature oligodendrocytes. Therefore, we questioned whether FGFR1 signaling may inhibit the capacity of OP cells to generate oligodendrocytes in a demyelinating disease model and whether genetically reducing FGFR1 signaling in oligodendrocyte lineage cells could enhance the capacity for remyelination. FGFR1 was found to be upregulated in the corpus callosum during cuprizone mediated demyelination and expressed on OP cells just prior to remyelination. Plp/CreERT:Fgfr1fl/fl mice were administered tamoxifen to induce conditional Fgfr1 deletion in oligodendrocyte lineage cells. Tamoxifen administration during chronic demyelination resulted in reduced FGFR1 expression in OP cells. OP proliferation and population size were not altered one week after tamoxifen treatment. Tamoxifen was then administered during chronic demyelination and mice were given a six week recovery period without cuprizone in the chow. After the recovery period, OP numbers were reduced and the number of mature oligodendrocytes was increased, indicating an effect of FGFR1 reduction on OP differentiation. Importantly, tamoxifen administration in Plp/CreERT:Fgfr1fl/fl mice significantly promoted remyelination and axon integrity. These results demonstrate a direct effect of FGFR1 signaling in oligodendrocyte lineage cells as inhibiting the repair capacity of OP cells following chronic demyelination in the adult CNS. 相似文献
15.
Unravelling the factors that can positively influence remyelination is one of the major challenges in multiple sclerosis research. Expression of the chemokine receptor CXCR2 on oligodendrocytes both in vitro and in MS lesions has suggested a possible role for CXCR2 in the recruitment of oligodendrocyte precursor cells (OPC). To investigate the function of CXCR2 during remyelination in vivo, we studied this receptor in cuprizone-induced demyelination and subsequent remyelination. We found that CXCR2 is constitutively expressed on OPC, whereas on macrophages/microglia CXCR2 is upregulated upon activation during demyelination. Hence, the expression of CXCR2 is differentially regulated in oligodendrocytes and macrophages/microglia. Furthermore, we subjected CXCR2-/- mice to the cuprizone model demonstrating that remyelination was not altered in comparison to wildtype controls. In addition, the number of OPC and the amount of microglial accumulation were similar in both CXCR2-/- and wildtype animals during the whole demyelination and remyelination process. These results suggest that despite expression on OPC and microglia CXCR2 plays only a minor role during remyelination. 相似文献
16.
Yang H Dixit VD Patel K Vandanmagsar B Collins G Sun Y Smith RG Taub DD 《Brain, behavior, and immunity》2008,22(8):1138-1145
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Hauke Schmidt Jenni Raasch Doron Merkler Florian Klinker Sandra Krauss Wolfgang Brück Marco Prinz 《Experimental neurology》2009,216(2):306-311
The type I interferons, interferon-beta and alpha (IFN-β, IFN-α), are widely used for the treatment of autoimmune demyelination in the central nervous system (CNS). Their effects on de- and remyelination through the broadly expressed type I IFN receptor (IFNAR), however, are highly speculative. In order to elucidate the role of endogenous type I interferons for myelin damage and recovery we induced toxic demyelination in the absence of IFNAR1. We demonstrate that IFNAR signalling was induced during acute demyelination since the cytokine IFN-β as well as the IFN-dependent genes IRF7, ISG15 and UBP43 were strongly upregulated. Myelin damage, astrocytic and microglia response, however, were not significantly reduced in the absence of IFNAR1. Furthermore, motor skills of IFNAR1-deficient animals during non-immune demyelination were unaltered. Finally, myelin recovery was found to be independent from endogenous IFNAR signalling, indicating a redundant role of this receptor for non-inflammatory myelin damage and repair. 相似文献
19.
Transport processes operating in astrocytes were examined by measuring unidirectional fluxes of42K and36Cl in primary cultures of mouse astrocytes, at steady-state with respect to ion composition. The total K+ uptake rate was 2025 nmol·mg−1 protein·min−1. This rate was not influenced by furosemide (2 mM), an inhibitor of Cl− uptake and K+-K+ exchange, or acetazolamide (0.1 mM), a carbonic anhydrase inhibitor. Ouabain (1 mM) inhibited the uptake rate by 541 nmol·mg−1·min−1. The equilibrated K+ content was determined to be 696 nmol·mg−1. The rate constant for efflux was 2.76 min−1. This equals an efflux rate of 1921 nmol·mg−1·min−1, i.e. a similar value as the influx. Furosemide and ouabain did not inhibit the efflux. The eequilibrated Cl− contents was found to be 167 nmol·mg−1 and it decreased in furosemide-treated cells to 68.1 nmol·mg−1. The total Cl− uptake was 35 nmol.mg−1 and it was inhibited by furosemide or bumetanide by 27 nmol·mg−1·min−1. The means resting membrane potential was found to be—77.4 mV. From these data we conclude: (1) that the K+ uptake rates are high, as can be expected from estimates based on literature data for K+ conductance in mammalian glial cells in situ; and (2) that the cells possess a very low relative Cl− permeability. 相似文献
20.
Summary This is a study of DNA synthesis of Schwann cells during the demyelination and the remyelination of peripheral nerves secondary to the intoxication of young rats with tellurium (Te). The3H-thymidine uptake of Schwann cells begins on day 4, reaches a zenith on day 7, and ends before day 20 on the Te diet despite continuation of the diet.The chronology of pathologic events is that myelin breakdown leading to segmental demyelination occurs first, followed within 24–48 h by the appearance of paralysis and by the beginning of DNA synthesis by the Schwann cells. A quantitative study on isolated nerve fiber preparations showed that more Schwann cells are produced than necessary to cope with the remyelination and that only one of four to six Schwann cells present in the demyelinated area at day 12 will participate in the remyelinating process.This study was supported by funds from NIH grant NS-12092 and from the Faculté de Médecine Paris-Sud 相似文献