| 1. |
- Andersson, Åsa, et al.
(författare)
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Pivotal Advance : HMGB1 expression in active lesions of human and experimental multiple sclerosis
- 2008
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Ingår i: Journal of Leukocyte Biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 84:5, s. 1248-1255
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Forskningsöversikt (refereegranskat)abstract
- Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the CNS, most frequently starting with a series of bouts, each followed by complete remission and then a secondary, progressive phase during which the neurological deficit increases steadily. The underlying molecular mechanisms responsible for disease progression are still unclear. Herein, we demonstrate that high mobility group box chromosomal protein 1 (HMGB1), a DNA-binding protein with proinflammatory properties, is evident in active lesions of MS and experimental autoimmune encephalomyelitis (EAE) and that HMGB1 levels correlate with active inflammation. Furthermore, the expression of the innate HMGB1 receptors--receptor for advanced glycation end products, TLR2, and TLR4--was also highly increased in MS and rodent EAE. Additionally, in vitro activation of rodent CNS-derived microglia and bone marrow-derived macrophages demonstrated that microglia were equally as capable as macrophages of translocating HMGB1 following LPS/IFN-gamma stimulation. Significant expression of HMGB1 and its receptors on accumulating activated macrophages and resident microglia may thus provide a positive feedback loop that amplifies the inflammatory response during MS and EAE pathogenesis.
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| 2. |
- Covacu, Ruxandra
(författare)
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Adult neural stem cells in neuroinflammation
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Adult neural stem cells (NSC) can be isolated from the subventricular zone (SVZ) of the lateral ventricles, the subgranular zone (SGZ) of the hippocampus and the central canal of the spinal cord. These cells are thought to have regenerative potential and pose important therapeutic possibilities in neuroinflammatory conditions such as Multiple Sclerosis (MS). The aim of this thesis was to investigate the function of these cells during neuroinflammation. To that end we employed both in vitro primary cultures of NSC and the experimental autoimmune encephalomyelitis (EAE) model. I. NSC generate neurons in demyelinated spinal cord lesions. In order to monitor NSC behaviour in EAE we labelled the endogenous NSC by injecting a lipophilic dye, DiI in the ventricle system of Dark Agouti rats. These rats were immunized to develop EAE and injected with BrdU to identify proliferating cells. We report that NSC proliferated and migrated to demyelinated lesions in the spinal cord of EAE diseased rats, where some of the cells started to express betaIIItubulin or NeuN. Ultimately, these NSC-derived neuronal-like cells could generate overshooting action potentials. II. Nitric oxide (NO) suppresses NSC-derived neurogenesis. In this study we used NSC cultures to analyse the effects of nitric oxide (NO) on NSC proliferation and differentiation. NO is produced within EAE and MS lesions and has been correlated with disease exacerbation in MS. We report that exposure of NSC to pathophysiological concentrations of NO diverted their differentiation potential from neurogenesis towards astrogliogenesis. Using immunocytochemistry we could demonstrate a lower percentage of betaIIItubulin-IR neurons but a higher percentage of O4-IR oligodendrocytes in NO-exposed cultures. The higher rate of gliogenesis in these cultures was also confirmed by western blotting for the astrocyte-specific protein GFAP and activated STAT1, a transcription factor involved in gliogenic differentiation. Moreover, the pro-neurogenic determinant neurogenin-2 was down-regulated subsequent to NO exposure, constituting a potential mechanism for the NO-mediated down-regulation of neurogenesis. III. High Mobility Group Box Protein 1 (HMGB1) expression correlates with inflammation in MS and EAE. In the third study we focused on the expression of the cytokine HMGB1 and its receptors RAGE, TLR-2 and TLR-4 in MS and EAE. Our interest in HMGB1 is related both to its cytokine function in inflammatory diseases and to its possible involvement in cell migration and differentiation. We detected cytoplasmic translocation of HMGB1, indicative of active release, in microglia and macrophages located in MS lesions. Moreover, the expression of HMGB1 and its receptors in immune cells isolated from the cerebrospinal fluid (CSF) of MS patients was significantly higher compared to cells from CSF of control patients. In EAE, an increased transcript level of HMGB1 correlated with higher disease severity. Finally, microglia cells could translocate HMGB1 to the cytoplasm, implying their ability to actively release this protein and indicating their potential contribution to inflammation. IV. TLR-2 and TLR-4 agonists induce TNFalpha release from NSC. TLR-2 and TLR-4 recognise bacterial moieties and can also ligate HMGB1. TLR activation in innate immune cells leads to release of inflammatory agents aimed at clearing invading pathogens. The connection between TLR and NSC originates from the Drosophila ortholog, Toll, which participates in neuronal patterning. Immunocytochemical investigations of primary NSC cultures revealed the presence of both TLR-2 and TLR-4 on these cells. Moreover, the expression of these receptors was differentially regulated by inflammatory conditions and cytokines. Agonist-induced TLR activation was not involved in differentiation or proliferation of NSC. Activation of these receptors prompted NSC to express the pro-inflammatory cytokine TNFalpha at both mRNA and protein levels. In conclusion, we demonstrated that inflammatory conditions can both promote and inhibit the ectodermal differentiation capacity of NSC, but also to yield them unexpected immune features.
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| 3. |
- Covacu, Ruxandra, et al.
(författare)
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Nitric oxide exposure diverts neural stem cell fate from neurogenesis towards astrogliogenesis
- 2006
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1066-5099 .- 1549-4918. ; 178, s. 268-268
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Regeneration of cells in the central nervous system is a process that might be affected during neurological disease and trauma. Because nitric oxide (NO) and its derivatives are powerful mediators in the inflammatory cascade, we have investigated the effects of pathophysiological concentrations of NO on neurogenesis, gliogenesis, and the expression of proneural genes in primary adult neural stem cell cultures. After exposure to NO, neurogenesis was downregulated, and this corresponded to decreased expression of the proneural gene neurogenin-2 and beta-III-tubulin. The decreased ability to generate neurons was also found to be transmitted to the progeny of the cells. NO exposure was instead beneficial for astroglial differentiation, which was confirmed by increased activation of the Janus tyrosine kinase/signal transducer and activator of transcription transduction pathway. Our findings reveal a new role for NO during neuroinflammatory conditions, whereby its proastroglial fate-determining effect on neural stem cells might directly influence the neuroregenerative process.
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| 4. |
- Danilov, Alexandre, et al.
(författare)
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Neurogenesis in the adult spinal cord in an experimental model of multiple sclerosis
- 2006
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Ingår i: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 23:2, s. 394-400
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Tidskriftsartikel (refereegranskat)abstract
- Multiple sclerosis is an inflammatory disease of the central nervous system characterized by inflammation, demyelination, axonal degeneration and accumulation of neurological disability. Previously, we demonstrated that stem cells constitute a possible endogenous source for remyelination. We now addressed the question of whether neurogenesis can occur in neuroinflammatory lesions. We demonstrated that, in experimental autoimmune encephalomyelitis, induced in rats 1,1'-dioctadecyl-6,6'-di(4sulphopentyl)-3,3,3',3'tetramethylindocarbocyani n(DiI)-labelled ependymal cells not only proliferated but descendants migrated to the area of neuroinflammation and differentiated into cells expressing the neuronal markers beta-III-tubulin and NeuN. Furthermore, these cells were immunoreactive for bromodeoxyuridine and PCNA, markers for cells undergoing cell proliferation. Using the whole-cell patch-clamp technique on freshly isolated 1, DiI-labelled cells from spinal cord lesions we demonstrated the ability of these cells to fire overshooting action potentials similar to those of immature neurones. We thus provide the first evidence for the initiation of neurogenesis in neuroinflammatory lesions in the adult spinal cord.
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| 5. |
- Johansson, Alina, et al.
(författare)
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miR-31 regulates energy metabolism and is suppressed in Tcells from patients with Sjögren's syndrome
- 2019
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Ingår i: European Journal of Immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 49:2, s. 313-322
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Tidskriftsartikel (refereegranskat)abstract
- Systemic autoimmune diseases are characterized by the overexpression of type I IFN stimulated genes, and accumulating evidence indicate a role for type I IFNs in these diseases. However, the underlying mechanisms for this are still poorly understood. To explore the role of type I IFN regulated miRNAs in systemic autoimmune disease, we characterized cellular expression of miRNAs during both acute and chronic type I IFN responses. We identified a Tcell-specific reduction of miR-31-5p levels, both after intramuscular injection of IFN and in patients with Sjogren's syndrome (SjS). To interrogate the role of miR-31-51p in Tcells we transfected human CD4(+) Tcells with a miR-31-5p inhibitor and performed metabolic measurements. This identified an increase in basal levels of glucose metabolism after inhibition of miR-31-5p. Furthermore, treatment with IFN- also increased the basal levels of human CD4(+) T-cell metabolism. In all, our results suggest that reduced levels of miR-31-5p in Tcells of SjS patients support autoimmune T-cell responses during chronic type I IFN exposure.
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