transforming-growth-factor-beta and Demyelinating-Diseases

The use of transgenic technology to over-express or prevent expression of genes encoding molecules related to inflammation has allowed direct examination of their role in experimental disease. This article reviews transgenic and knockout models of CNS demyelinating disease, focusing primarily on the autoimmune disease multiple sclerosis, as well as conditions in which an inflammatory response makes a secondary contribution to tissue injury or repair, such as neurodegeneration, ischemia and trauma.

Topics: Animals; Central Nervous System; Chemokines; Clinical Trials as Topic; Cytokines; Demyelinating Diseases; Humans; Interferon-gamma; Models, Genetic; Multiple Sclerosis; Th2 Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

IFN beta-1b reduces the frequency of major multiple sclerosis attacks by 50 percent. Serial MRI scanning over the course of the clinical trial that led to approval of the agent revealed a significant lessening both in disease activity and in accumulating burden of disease in IFN beta-1b-treated patients compared to placebo-treated controls. The mechanism by which IFN beta-1b exerts its beneficial effect in multiple sclerosis is unknown. T suppressor cell function fails during MS attacks and is persistently subnormal in multiple sclerosis patients with progressive disease. IFN beta-1b partially restores suppressor function in multiple sclerosis patients. IFN beta-1b also inhibits release of lymphotoxin, tumor necrosis factor, and interferon gamma, at least in vitro. All three cytokines are toxic to oligodendrocytes. In contrast; production of transforming growth factor beta-1 (TGF beta 1) is increased by IFN beta-1b. TGF beta 1 is an immunosuppressive cytokine. All of the above listed actions of IFN beta-1b could contribute to its beneficial effect. Perhaps all do.

Topics: Demyelinating Diseases; Humans; Interferon beta-1a; Interferon beta-1b; Interferon-beta; Interferon-gamma; Magnetic Resonance Imaging; Multiple Sclerosis; Recombinant Proteins; Transforming Growth Factor beta

Topics: Animals; Corpus Callosum; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Interleukin-10; Mesenchymal Stem Cells; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Sheath; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Proregenerative responses are required for the restoration of nervous-system functionality in demyelinating diseases such as multiple sclerosis (MS). Yet, the limiting factors responsible for poor CNS repair are only partially understood. Here, we test the impact of a Western diet (WD) on phagocyte function in a mouse model of demyelinating injury that requires microglial innate immune function for a regenerative response to occur. We find that WD feeding triggers an ageing-related, dysfunctional metabolic response that is associated with impaired myelin-debris clearance in microglia, thereby impairing lesion recovery after demyelination. Mechanistically, we detect enhanced transforming growth factor beta (TGFβ) signalling, which suppresses the activation of the liver X receptor (LXR)-regulated genes involved in cholesterol efflux, thereby inhibiting phagocytic clearance of myelin and cholesterol. Blocking TGFβ or promoting triggering receptor expressed on myeloid cells 2 (TREM2) activity restores microglia responsiveness and myelin-debris clearance after demyelinating injury. Thus, we have identified a druggable microglial immune checkpoint mechanism regulating the microglial response to injury that promotes remyelination.

Topics: Aging; Animals; Cholesterol; Demyelinating Diseases; Diet; Diet, Western; Immunity, Innate; Liver X Receptors; Lysophosphatidylcholines; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Microglia; Myelin Sheath; Phagocytes; Receptors, Immunologic; Transforming Growth Factor beta

Mesenchymal stem cells (MSCs) have a notable potential to modulate immune responses and protect the central nervous system (CNS), mostly by secreting factors that affect inflammation. MSCs have the ability to improve several autoimmune diseases in animal models including multiple sclerosis (MS). MS is a disease of the CNS among adult humans and it is characterized by demyelination, neuroinflammation and gliosis. In this study, we first induced chronic demyelination by cuprizone, followed by intraventricular injection of MSC. Our results showed that MSC significantly decreased microgliosis and astrocytosis by secreting cytokines that have neuroprotective activity including TGF-β and CX3CL1. Also, downregulation of IL-1β and TNF-α as inflammatory chemokines was seen along with decreased astrocytes and microglia activation. Finally, these results showed that trophic factors secreted by MSC can increase oligodendrocyte population and remyelination rate by reducing pro-inflammatory factors. These findings demonstrate that MSC could decrease inflammation, gliosis and demyelination with neuroprotective and immunomodulating properties in chronic cuprizone demyelination model. Therefore MSC transplantation can be considered as a suitable approach for enhancing myelination and reducing inflammation in diseases such as MS.

Topics: Animals; Chemokine CX3CL1; Cuprizone; Cytokines; Demyelinating Diseases; Male; Mesenchymal Stem Cells; Mice; Neuroglia; Transforming Growth Factor beta

The cytokine transforming growth factor-β (TGF-β) regulates the development and homeostasis of several tissue-resident macrophage populations, including microglia. TGF-β is not critical for microglia survival but is required for the maintenance of the microglia-specific homeostatic gene signature

Topics: Animals; Brain; Demyelinating Diseases; Macrophages; Mice; Signal Transduction; Spinal Cord; Transforming Growth Factor beta

Idiopathic optic neuritis (ION) is an inflammation of the optic nerve that may result in a complete or partial loss of vision. ION is usually due to the immune attack of the myelin sheath covering the optic nerve. ION acts frequently as the first symptoms of multiple sclerosis (MS) and neuromyelitis optica (NMO), or other inflammatory demyelinating disorders. The pathogenic progression of ION remains unclear. Experimental autoimmune encephalitis (EAE) is a commonly used model of idiopathic inflammatory demyelinating disorders (IIDDs); the optic nerve is affected in EAE as well. The specific mediators of demyelination in optic neuritis are unknown. Recent studies have indicated what T-cell activation in peripheral blood is associated with optic neuritis pathogenesis. The object of the present study was to determine whether certain cytokines (IL-6, IL-17A, and IL-23) and AQP4 contribute to the demyelinating process using EAE model. We have found that IL-6R, AQP4 and IL-23R are significantly increased in mRNA and protein levels in optic nerves in EAE mice compared to control mice; serum AQP4, IL-6, IL-17A, IL-23 are increased whereas transforming growth factor beta (TGF-β) is decreased in EAE mice. These results suggest that AQP4 and selective cytokines in serum are associated with ION pathogenesis in the animal model, and these results shine light for future clinical diagnosis as potential biomarkers in ION patients.

Topics: Animals; Aquaporin 4; Biomarkers; Cytokines; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Evoked Potentials, Visual; Female; Interleukin-17; Interleukin-23; Interleukin-6; Mice, Inbred C57BL; Optic Nerve; Optic Neuritis; Predictive Value of Tests; Prognosis; Transforming Growth Factor beta; Up-Regulation

Inhibition of remyelination is part of the complex problem of persistent dysfunction after spinal cord injury (SCI), and residual myelin debris may be a factor that inhibits remyelination. Phagocytosis by microglial cells and by macrophages that migrate from blood vessels plays a major role in the clearance of myelin debris. The object of this study was to investigate the mechanisms underlying the failure of significant remyelination after SCI.. The authors investigated macrophage recruitment and related factors in rats by comparing a contusion model (representing contusive SCI with residual myelin debris and failure of remyelination) with a model consisting of chemical demyelination by lysophosphatidylcholine (representing multiple sclerosis with early clearance of myelin debris and remyelination). The origin of infiltrating macrophages was investigated using mice transplanted with bone marrow cells from green fluorescent protein-transfected mice. The changes in levels of residual myelin debris and the infiltration of activated macrophages in demyelinated lesions were investigated by immunostaining at 2, 4, and 7 days postinjury. To investigate various factors that might be involved, the authors also investigated gene expression of macrophage chemotactic factors and adhesion factors.. Activated macrophages coexpressing green fluorescent protein constituted the major cell population in the lesions, indicating that the macrophages in both models were mainly derived from the bone marrow, and that very few were derived from the intrinsic microglia. Immunostaining showed that in the contusion model, myelin debris persisted for a long period, and the infiltration of macrophages was significantly delayed. Among the chemotactic factors, the levels of monocyte chemoattractant protein-1 and granulocyte-macrophage colony-stimulating factor were lower in the contusion model at 2 and 4 days postinjury.. The results suggest that the delayed infiltration of activated macrophages is related to persistence of myelin debris after contusive SCI, resulting in the inhibition of remyelination.

Topics: Animals; Bone Marrow Transplantation; Chemokine CCL2; Contusions; Cytokines; Demyelinating Diseases; Disease Models, Animal; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Intercellular Adhesion Molecule-1; Macrophage Activation; Macrophage Inflammatory Proteins; Macrophages; Mice; Mice, Inbred C57BL; Microglia; Multiple Sclerosis; Myelin Sheath; Phagocytosis; Platelet Endothelial Cell Adhesion Molecule-1; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries; Transforming Growth Factor beta; Wound Healing

We investigated the effects of bone morphogenetic protein-2 (BMP-2) and some other BMPs on regeneration of peripheral motor nerves in vivo. The facial nerves of 24 New Zealand rabbits were crushed to examine a series of retrograde changes in the facial nuclei and axons, in what has been called the "axon reaction". The facial nerves of the experimental group were treated with epineurial coaptation and BMP-2 after the injury. Nerves not treated with BMP-2 were regarded as controls. The expression of BMP-2 was investigated by in situ hybridisation in the neurons of facial nuclei. The electrophysiology, image analysis and transmission electron microscopy were used to evaluate the level of the recovery of facial nerves. The results showed that the axons in the experimental group were thicker and denser than those in the control group four weeks later. The expression of BMP-2 in the neurons of facial nuclei increased after injury. The electron microscopic observations showed that the axons' degeneration in the experimental group was less than that in the control group. Despite the morphological difference between the two groups, there was no apparent difference between them in nerve conduction velocity. These findings suggest that BMP-2 might be involved in the regeneration of facial nerves, and might function as a potential neurotrophic factor.

Topics: Animals; Axons; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins; Brain Stem; Demyelinating Diseases; Electromyography; Facial Nerve Injuries; Image Processing, Computer-Assisted; Lysosomes; Microscopy, Electron, Transmission; Mitochondria; Motor Neurons; Myelin Sheath; Nerve Degeneration; Nerve Growth Factors; Nerve Regeneration; Neural Conduction; Rabbits; Recombinant Proteins; Recovery of Function; Schwann Cells; Transforming Growth Factor beta

Schwann cells differentiate in vivo in response to contact with axons, and cAMP simulates some of these aspects of differentiation in vitro, particularly morphologic changes and expression of certain phenotypic molecules. Unfractionated inflammatory cytokines inhibit cAMP-induced Schwann cell expression of galactolipids (Gal). We sought to identify which cytokines were responsible for this inhibition and to determine whether other phenotypic indicators of Schwann cell differentiation were also affected. Neonatal rat Schwann cells were incubated in vitro with 1 mM 8 Bromo cAMP (8 Br cAMP) with or without the addition of interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-6, tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), or transforming growth factor-beta (TGF-beta). Cells were then examined for morphologic changes and for expression of surface Gal and low-affinity nerve growth factor receptor (NGFRp75), employing indirect immunofluorescence. 8 Br cAMP induced Schwann cell upregulation of Gal, downregulation of NGFRp75, and the cells became enlarged and somewhat amorphous and irregular in appearance. Cells treated with IFN-gamma or TNF-alpha alone were more bipolar and more evenly distributed on coverslips than were control cells, whereas TGF-beta alone induced elongated cells often in a swirling pattern. None of the cytokines alone induced upregulation of Gal or downregulation of NGFRp75. TNF-alpha, IFN-gamma, and TGF-beta inhibited the 8 Br cAMP-induced morphologic changes, as well as the upregulation of Gal and downregulation of NGFRp75. The other cytokines had no effects on Gal or NGFRp75 expression. Thus, these three cytokines, which are present in inflammatory lesions in the peripheral nervous system, are capable of inhibiting Schwann cell differentiation.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Animals; Animals, Newborn; Cell Differentiation; Cells, Cultured; Cyclic AMP; Cytokines; Demyelinating Diseases; Dose-Response Relationship, Drug; Down-Regulation; Galactolipids; Glycolipids; Inflammation; Interferon-gamma; Peripheral Nervous System; Rats; Rats, Sprague-Dawley; Receptor, Nerve Growth Factor; Schwann Cells; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha; Up-Regulation

Canine distemper virus (CDV) infection in dogs is commonly associated with demyelinating leukoencephalitis (DL). Although the mechanism of primary demyelination in distemper remains undetermined recent studies showed a direct virus-induced cytolysis in early non-inflammatory and immune-mediated mechanisms in inflammatory lesions. To further investigate the pathogenesis of this morbillivirus-induced demyelination the expression of a variety of cytokine mRNA species (interleukin (IL)-1beta, IL-2, IL-6, IL-10, IL-12, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, and interferon (IFN)-gamma in cerebrospinal fluid cells of 12 dogs with CDV encephalitis was investigated employing reverse transcription-polymerase chain reaction (RT-PCR) and these findings were correlated to the type of CNS lesions. Neuropathology revealed the whole spectrum of distemper DL lesions from acute to chronic alterations, however, most plaques lacked active demyelination. Three control animals were devoid of any cytokine expression, whereas in distemper animals IL-10 transcripts were found in nine dogs with acute and chronic lesions. IL-6, TNF, and TGF mRNA was found in six, four, and three animals, respectively. IL-12 and IFN-gamma, suggestive of a TH1-like dominated immune response, were detected only in one animal with chronic lesions. Summarized, TNF and IL-6, associated with disease exacerbation, and IL-10 and TGF, indicative of remission, were often observed simultaneously in distemper DL and could not be assigned to a specific disease stage. However IL-10 mRNA remained the most frequently detected cytokine indicating a stage of inactivity in most animals investigated.

Topics: Animals; Brain; Demyelinating Diseases; Disease Models, Animal; Distemper; Distemper Virus, Canine; DNA Primers; Dogs; Encephalitis, Viral; Gene Expression; Interferon-gamma; Interleukin-1; Interleukin-10; Interleukin-12; Interleukin-2; Interleukin-6; Multiple Sclerosis; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Topics: Adjuvants, Immunologic; Demyelinating Diseases; Humans; Immunity, Cellular; Immunoglobulins, Intravenous; Plasma Exchange; Polyradiculoneuropathy; Transforming Growth Factor beta