TREM-2 Drives Development of Multiple Sclerosis by Promoting Pathogenic Th17 Polarization / 神经科学通报·英文版

Multiple sclerosis (MS) is a neuroinflammatory demyelinating disease, mediated by pathogenic T helper 17 (Th17) cells. However, the therapeutic effect is accompanied by the fluctuation of the proportion and function of Th17 cells, which prompted us to find the key regulator of Th17 differentiation in MS. Here, we demonstrated that the triggering receptor expressed on myeloid cells 2 (TREM-2), a modulator of pattern recognition receptors on innate immune cells, was highly expressed on pathogenic CD4-positive T lymphocyte (CD4+ T) cells in both patients with MS and experimental autoimmune encephalomyelitis (EAE) mouse models. Conditional knockout of Trem-2 in CD4+ T cells significantly alleviated the disease activity and reduced Th17 cell infiltration, activation, differentiation, and inflammatory cytokine production and secretion in EAE mice. Furthermore, with Trem-2 knockout in vivo experiments and in vitro inhibitor assays, the TREM-2/zeta-chain associated protein kinase 70 (ZAP70)/signal transducer and activator of transcription 3 (STAT3) signal axis was essential for Th17 activation and differentiation in EAE progression. In conclusion, TREM-2 is a key regulator of pathogenic Th17 in EAE mice, and this sheds new light on the potential of this therapeutic target for MS.

Progress in Mechanism of Astragalus membranaceus and Its Chemical Constituents on Multiple Sclerosis / 中国结合医学杂志

The primary chemical components of Astragalus membranaceus include polysaccharides, saponins, flavonoids, and amino acids. Recent studies have shown that Astragalus membranaceus has multiple functions, including improving immune function and exerting antioxidative, anti-radiation, anti-tumor, antibacterial, antiviral, and hormone-like effects. Astragalus membranaceus and its extracts are widely used in clinical practice because they have obvious therapeutic effects against various autoimmune diseases and relatively less adverse reaction. Multiple sclerosis (MS) is an autoimmune disease of central nervous system (CNS), which mainly caused by immune disorder that leads to inflammatory demyelination, inflammatory cell infiltration, and axonal degeneration in the CNS. In this review, the authors analyzed the clinical manifestations of MS and experimental autoimmune encephalomyelitis (EAE) and focused on the efficacy of Astragalus membranaceus and its chemical components in the treatment of MS/EAE.

The immunomodulator glatiramer acetate influences spinal motoneuron plasticity during the course of multiple sclerosis in an animal model

The immunomodulador glatiramer acetate (GA) has been shown to significantly reduce the severity of symptoms during the course of multiple sclerosis and in its animal model - experimental autoimmune encephalomyelitis (EAE). Since GA may influence the response of non-neuronal cells in the spinal cord, it is possible that, to some extent, this drug affects the synaptic changes induced during the exacerbation of EAE. In the present study, we investigated whether GA has a positive influence on the loss of inputs to the motoneurons during the course of EAE in rats. Lewis rats were subjected to EAE associated with GA or placebo treatment. The animals were sacrificed after 15 days of treatment and the spinal cords processed for immunohistochemical analysis and transmission electron microscopy. A correlation between the synaptic changes and glial activation was obtained by performing labeling of synaptophysin and glial fibrillary acidic protein using immunohistochemical analysis. Ultrastructural analysis of the terminals apposed to alpha motoneurons was also performed by electron transmission microscopy. Interestingly, although the GA treatment preserved synaptophysin labeling, it did not significantly reduce the glial reaction, indicating that inflammatory activity was still present. Also, ultrastructural analysis showed that GA treatment significantly prevented retraction of both F and S type terminals compared to placebo. The present results indicate that the immunomodulator GA has an influence on the stability of nerve terminals in the spinal cord, which in turn may contribute to its neuroprotective effects during the course of multiple sclerosis.

Compromiso neuronal en esclerosis multiple / Neuronal injury in multiple sclerosis

La esclerosis múltiple (EM) ha sido considerada clásicamente como una enfermedad desmielinzante. Si bien el compromiso neurodegenerativo fue previamente descripto, sólo recientemente ha sido enfatizado. Por estudiosos recientes se ha identificado la degeneración axonal como el mayor determinante de discapacidad neurológica irreversible en pacientes con EM. El daño axonal se inicia tempranamente y permanece silente durante años, la discapacidad neurológica se desarrolla cuando se alcanza cierto umbral de pérdida axonal y los mecanismos de compensación se agotan. Se han propuesto tres hipótesis para explicar el daño axonal: 1) El daño es causado por un proceso inflamatorio, 2) Existe una excesiva acumulación de Ca2+ intra-axonal, 3) Los axones desmienlinizados evolucionan a un proceso degenerativo producto de la falta de soporte trófico provisto por la mielina o células formadoras de mielina. Si bien la EM fue tradicionalmente considerada como una enfermedad de la sustancia blanca, el proceso de desmielinización tambiém ocurre en la corteza cerebral

The concept of multiple sclerosis (MS) as a demyelinating disease is deeply ingrained. Although the existence of a neurodegenerative component has always been apparent, it has only recently become emphasized. Thus, in recent years several studies have identified axonal degeneration as the major determinant of irreversible neurological disability in patients with MS. Axonal injury begins at disease onset and remains clinically silent for many years; irreversible neurological disability develops when a threshold of axonal loss is reached and CNS compensatory mechanisms are exhausted. The precise mechanisms of axonal loss are poorly understood, and three hypotheses have been proposed: 1) The damage is caused by an inflammatory process, 2) There is an excessive accumulation of intra-axonal Ca2+, 3) Demyelinated axons undergo degeneration due to lack of trophic support by myelin, or myelin forming cells. Although MS has traditionally been regarded as a disease of white matter, demyelination can also occur in the cerebral cortex. Cortical lesions exhibit neuronal injury represented by dendritic and axonal transection as well as neuronal apoptosis. Because conventional nuclear magnetic resonance (NMR) is limited in its ability to provide specific information about axonal pathology in MS, new techniques such as, diffusion-weighted MRI, proton magnetic resonance spectroscopy, functional MRI, as well as novel techniques designed to measure atrophy have been developed to monitor MS evolution. Recognition that MS is in part a neurodegenerative disease should trigger critical rethinking on the pathogenic mechanisms of this disease and provides new targets for a rational treatment

Embryonic Intermediate Filaments, Nestin and Vimentin, Expression in the Spinal Cords of Rats with Experimental Autoimmune Encephalomyelitis

Intermediate filaments, including nestin and vimentin, are found in specific cell types in central nervous system (CNS) tissues, particularly immature glial cells and multipotent progenitor cells. In the present study, the expression patterns of nestin and vimentin in the spinal cords of rats with experimental autoimmune encephalomyelitis (EAE) and the response of cells containing filaments against acute autoimmune injury were examined by immunohistochemistry. Nestin immunostaining was only weakly detected in vascular endothelial cells but not in any cell types in the spinal cord in normal and adjuvant-immunized rats. At the peak stage of EAE, nestin-immunoreativity was recognized in some astrocytes in the gray matter and white matter. Vimentin was immunopositive in some astrocytes and macrophages in EAE lesions, while vimentin was normally detected in ependymal cells of central canals in the rat spinal cords.We postulate that normal animals may contain multipotent progenitor cells in the spinal cord parenchyma as well as in the subpial lesion and ependyma. Multipotent progenitor cells may activate to transform into necessary cells, including neurons, astrocytes or oligodendrocytes, depending on CNS needs. Appropriate control of progenitor cells in the injured CNS is an alternative choice for CNS remodeling.

Immunohistochemical Localization of Bcl-2 in the Spinal Cords of Rats with Experimental Autoimmune Encephalomyelitis

We examined the localization of the anti-apoptotic molecule Bcl-2 in the spinal cords of Lewis rats with experimental autoimmune encephalomyelitis (EAE). Western blot analysis showed that Bcl-2 was constitutively expressed in normal spinal cords, and weakly increased in response to complete Freund's adjuvant(CFA) immunization. In EAE, with infiltration of inflammatory cells into spinal cords, Bcl-2 declined during the peak stage and further decreased during the recovery stage. Immunohistochemically, some neurons and glial cells constitutively expressed Bcl-2 in normal rat spinal cords. In the spinal cords of rats with EAE, Bcl-2 was also immunoreacted in some perivascular inflammatory cells while some brain cells, such as neurons and GFAP (+) astrocytes showed less Bcl-2 immunoreaction.These findings suggest that in EAE, Bcl-2 expression in the CNS host cells decreases with CNS inflammation, possibly progressing to cell death in some cases, while the survival of host cells, including neurons, astrocytes, and some inflammatory cells, is associated with activation of the anti-apoptotic molecule Bcl-2. Taking all into considerations, its is postulated that Bcl-2 either beneficially or detrimentally functions in some host cells depending on the activation stage of each cell type.

A study on demyelinating effect of galactocerebroside in experimental allergic encephalomyelitis

An experimental allergic encephalomyelitis was induced by bovine myelin basic protein (MBP) and bovine galactocerebroside (GC) on male guinea pigs. Animals were divided into five experimental and one control groups. Among the five experimental groups, three were inoculated with 75 micrograms, 150 micrograms and 300 micrograms of MBP, respectively, to see the dose dependency of demyelination. The fourth group was inoculated with mixture of 75 micrograms of MBP and 180 micrograms of GC and the fifth group with 180 micrograms GC. All inocula was injected intradermally in emulsion state mixed with equal amount of complete Freund adjuvant. Control group was injected with adjuvant only. Clinical symptoms began to appear from 15th day after inoculation and animals were sacrificed on maximum neurologic deficit or 4 to 5 days after the onset of symptoms. Demyelination was observed in 6 out of 8 animals inoculated with MBP/GC mixture, while only 3 out of 24 animals inoculated with various dosage of MBP showed demyelination. The difference was statistically significant. Serum antibodies to MBP and GC were measured by ELISA method. All of the eight animals inoculated with MBP/GC mixture and two animals inoculated with GC had low titer of anti-GC antibodies, while all animals inoculated with MBP, MBP alone or MBP/GC mixture, had high titer of anti-MBP antibodies. Therefor it is concluded that the demyelination is augmented by GC and is not significantly dose-dependent on MBP.

A study on demyelinating effect of galactocerebroside in experimental allergic encephalomyelitis

An experimental allergic encephalomyelitis was induced by bovine myelin basic protein (MBP) and bovine galactocerebroside (GC) on male guinea pigs. Animals were divided into five experimental and one control groups. Among the five experimental groups, three were inoculated with 75 micrograms, 150 micrograms and 300 micrograms of MBP, respectively, to see the dose dependency of demyelination. The fourth group was inoculated with mixture of 75 micrograms of MBP and 180 micrograms of GC and the fifth group with 180 micrograms GC. All inocula was injected intradermally in emulsion state mixed with equal amount of complete Freund adjuvant. Control group was injected with adjuvant only. Clinical symptoms began to appear from 15th day after inoculation and animals were sacrificed on maximum neurologic deficit or 4 to 5 days after the onset of symptoms. Demyelination was observed in 6 out of 8 animals inoculated with MBP/GC mixture, while only 3 out of 24 animals inoculated with various dosage of MBP showed demyelination. The difference was statistically significant. Serum antibodies to MBP and GC were measured by ELISA method. All of the eight animals inoculated with MBP/GC mixture and two animals inoculated with GC had low titer of anti-GC antibodies, while all animals inoculated with MBP, MBP alone or MBP/GC mixture, had high titer of anti-MBP antibodies. Therefor it is concluded that the demyelination is augmented by GC and is not significantly dose-dependent on MBP.