Novel role for SLPI in MOG-induced EAE revealed by spinal cord expression analysis
| Autor: | Andreas Steinbrecher, Thomas Stempfl, Ludwig Aigner, Ingo Kleiter, Xiomara Pedré, André M. Mueller, Gerhard Giegerich, Sebastien Couillard-Despres |
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| Rok vydání: | 2008 |
| Předmět: |
Encephalomyelitis
Autoimmune Experimental Transcription Genetic Cellular differentiation Encephalomyelitis Immunology Polymerase Chain Reaction lcsh:RC346-429 Myelin oligodendrocyte glycoprotein Transcriptome Cellular and Molecular Neuroscience Synaptotagmins medicine Animals Paralysis Secretory Leukocyte Peptidase Inhibitor Deoxyribonucleases Type II Site-Specific lcsh:Neurology. Diseases of the nervous system Oligonucleotide Array Sequence Analysis biology General Neuroscience Macrophages Research Experimental autoimmune encephalomyelitis medicine.disease Molecular biology Neural stem cell Oligodendrocyte Rats Myelin-Associated Glycoprotein medicine.anatomical_structure Neurology Spinal Cord biology.protein Female Myelin-Oligodendrocyte Glycoprotein Microglia Myelin Proteins SLPI |
| Zdroj: | Journal of Neuroinflammation Journal of Neuroinflammation, Vol 5, Iss 1, p 20 (2008) |
| ISSN: | 1742-2094 |
| Popis: | Background Experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte protein (MOG) in female Dark Agouti (DA) rats is a chronic demyelinating animal model of multiple sclerosis (MS). To identify new candidate molecules involved in the evolution or repair of EAE-lesions we used Affymetrix oligonucleotide microarrays to compare the spinal cord transcriptome at the peak of EAE, during remission and at the first relapse with healthy DA rats. Methods Untreated DA rats and DA rats immunised with MOG protein were sacrificed at defined time points. Total RNA was isolated from spinal cord tissue and used for hybridization of Affymetrix rat genome arrays RG U34 A-C. Selected expression values were confirmed by RealTime PCR. Adult neural stem cells were incubated with recombinant secretory leukocyte protease inhibitor (SLPI). Proliferation was assessed by BrdU incorporation, cyclin D1 and HES1 expression by RealTime PCR, cell differentiation by immunofluorescence analysis and IkappaBalpha degradation by Western blot. Results Among approximately 26,000 transcripts studied more than 1,100 were differentially regulated. Focussing on functional themes, we noticed a sustained downregulation of most of the transcripts of the cholesterol biosynthesis pathway. Furthermore, we found new candidate genes possibly contributing to regenerative processes in the spinal cord. Twelve transcripts were solely upregulated in the recovery phase, including genes not previously associated with repair processes. Expression of SLPI was upregulated more than hundredfold during EAE attack. Using immunohistochemistry, SLPI was identified in macrophages, activated microglia, neuronal cells and astrocytes. Incubation of adult neural stem cells (NSC) with recombinant SLPI resulted in an increase of cell proliferation and of differentiation towards oligodendrocytes. These processes were paralleled by an upregulation of the cell-cycle promotor cyclin D1 and a suppression of the cell differentiation regulator HES1. Finally, SLPI prevented the degradation of IkappaBalpha, which may explain the suppression of the cell differentiation inhibitor HES1 suggesting a possible mechanism of oligodendroglial differentiation. Conclusion We identified novel features of gene expression in the CNS during EAE, in particular the suppression of genes of cholesterol biosynthesis and a strong upregulation of SLPI, a gene which is for the first time associated with autoimmune inflammation. The capacity of SLPI to increase proliferation of adult NSC and of oligodendroglial differentiation suggests a novel role for SLPI in the promotion of tissue repair, beyond its known functions in the prevention of tissue damages by protease inhibition damage and modulation of inflammatory reactions. |
| Databáze: | OpenAIRE |
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