Multiple sclerosis（MS） is a classical inflammatory demyelinating disease of the central nervous system（CNS）. Microglia are the main resident immune cells in the CNS and are closely associated with the pathogenesis...Multiple sclerosis（MS） is a classical inflammatory demyelinating disease of the central nervous system（CNS）. Microglia are the main resident immune cells in the CNS and are closely associated with the pathogenesis of MS.In the present study, we found that mi R-30 a was highly expressed in jellyfish-like microglia in chronic active lesions of MS patients, as well as in the microglia of mice with experimental autoimmune encephalomyelitis（EAE） at the chronic phase. In vitro, the conditioned supernatant of mouse microglia overexpressing miR-30 a promoted the apoptosis of oligodendrocyte precursor cells（OPCs）, and inhibited OPC differentiation. In vivo, overexpressing miR-30 a in transplanted microglia exacerbated the progression of EAE.Overexpression and knock-down experiments in primary cultured mouse microglia showed that mi R-30 a increased the expression of IL-1 b and i NOS, which are pro-inflammatory, while inhibiting the expression of Ym-1 and CD206.Mechanistically, mi R-30 a inhibited the expression of Ppargc1 b, which is the co-activator of peroxisome proliferator-activated receptor gamma, resulting in pro-inflammatory effects. Our work shows that mi R-30 a is an important regulator of the inflammatory response in microglia, and may be a promising therapeutic target for inflammatory diseases like MS in the CNS.展开更多
The transcription factor nuclear factor κB（NF-κB） plays major roles in inflammatory diseases through regulation of inflammation and cell viability.Multiple sclerosis（MS） is a chronic inflammatory demyelinating a...The transcription factor nuclear factor κB（NF-κB） plays major roles in inflammatory diseases through regulation of inflammation and cell viability.Multiple sclerosis（MS） is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system（CNS）.It has been shown that NF-κB is activated in multiple cell types in the CNS of MS patients,including T cells,microglia/macrophages,astrocytes,oligodendrocytes,and neurons.Interestingly,data from animal model studies,particularly studies of experimental autoimmune encephalomyelitis,have suggested that NF-κB activation in these individual cell types has distinct effects on the development of MS.In this review,we will cover the current literature on NF-κB and the evidence for its role in the development of MS and its animal model experimental autoimmune encephalomyelitis.展开更多
Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain,spinal cord and optic nerve leading to demyelination....Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain,spinal cord and optic nerve leading to demyelination.Focal demyelination is associated with relapsing-remitting multiple sclerosis,while progressive forms of the disease show axonal degeneration and neuronal loss.The tests currently used in the clinical diagnosis and management of multiple sclerosis have limitations due to specificity and sensitivity.MicroRNAs(miRNAs)are dysregulated in many diseases and disorders including demyelinating and neuroinflammatory diseases.A review of recent studies with the experimental autoimmune encephalomyelitis animal model(mostly female mice 6–12 weeks of age)has confirmed miRNAs as biomarkers of experimental autoimmune encephalomyelitis disease and importantly at the pre-onset(asymptomatic)stage when assessed in blood plasma and urine exosomes,and spinal cord tissue.The expression of certain miRNAs was also dysregulated at the onset and peak of disease in blood plasma and urine exosomes,brain and spinal cord tissue,and at the post-peak(chronic)stage of experimental autoimmune encephalomyelitis disease in spinal cord tissue.Therapies using miRNA mimics or inhibitors were found to delay the induction and alleviate the severity of experimental autoimmune encephalomyelitis disease.Interestingly,experimental autoimmune encephalomyelitis disease severity was reduced by overexpression of miR-146a,miR-23b,miR-497,miR-26a,and miR-20b,or by suppression of miR-182,miR-181c,miR-223,miR-155,and miR-873.Further studies are warranted on determining more fully miRNA profiles in blood plasma and urine exosomes of experimental autoimmune encephalomyelitis animals since they could serve as biomarkers of asymptomatic multiple sclerosis and disease course.Additionally,studies should be performed with male mice of a similar age,and with aged male and female mice.展开更多
Objective： To study the effects of Bushen Yisui Capsule（补肾益髓胶囊, BSYSC） on the oligodendrocyte lineage genes（Olig） 1 and Olig2 in C57BL/6 mice with experimental autoimmune encephalomyelitis（EAE） in order t...Objective： To study the effects of Bushen Yisui Capsule（补肾益髓胶囊, BSYSC） on the oligodendrocyte lineage genes（Olig） 1 and Olig2 in C57BL/6 mice with experimental autoimmune encephalomyelitis（EAE） in order to explore the remyelination effect of BSYSC. Methods： The mice were randomly divided into normal control（NC）, EAE model（EAE-M）, prednisone acetate（PA, 6 mg/kg）, BSYSC high-dose（3.02 g/kg） and BSYSC low-dose（1.51 g/kg） groups. The mice were induced by immunization with myelin oligodendrocyte glycoprotein（MOG） 35-55. The neurological function scores were assessed once daily. The pathological changes in mice brains were observed with hematoxylin-eosin（HE） staining and transmission electron microscope（TEM）. The protein expressions of myelin basic protein（MBP）, Olig1 and Olig2 in brains were measured by immunohistochemistry. The m RNA expressions of Olig1 and Olig 2 was also determined by quantitative real-time polymerase chain reaction. Results： Compared with the EAE-M mice,（1） the neurological function scores were significantly decreased in BSYSC-treated mice on days 22 to 40（P〈0.01）;（2） the inflammatory cells and demyelination in brains were reduced in BSYSC-treated EAE mice;（3） the protein expression of MBP was markedly increased in BSYSC-treated groups on day 18 and 40 respectively（P〈0.05 or P〈0.01）;（4） the protein expression of Olig1 was increased in BSYSC（3.02 g/kg）-treated EAE mice on day 40（P〈0.01）. Protein and m RNA expression of Olig2 was increased in BSYSC-treated EAE mice on day 18 and 40（P〈0.01）. Conclusion： The effects of BSYSC on reducing demyelination and promoting remyelination might be associated with the increase of Olig1 and Olig2.展开更多
Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating rheumatic and arthritic diseases. In our previous studies, we...Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating rheumatic and arthritic diseases. In our previous studies, we found that sinomenine reduced cellular infiltration within the spinal cord and alleviated experimental autoimmune encephalomyelitis （EAE） in rats. In this study, we further investigated the mechanisms of sinomenine treatment in EAE rats. In EAE rats, treatment with sinomenine exerted an anti-inducible NO synthase （anti-iNOS） effect, which is related to the reductions of Thl cytokine interferon-y （IFN-7） and its transcription factor, T-bet, in spinal cords. Moreover, sinomenine treatment of splenocytes stimulated with anti-CD3 antibody and recombinant rat in- terleukin 12 reduced the expression of T-bet and IFN-y in vitro and also reduced the capability of supernatants of splenocyte culture to induce iNOS expression by primary astrocytes. However, sinomenine had no direct inhibito- ry effect on iNOS produced by astrocytes cultured with IFN-y and tumor necrosis factor α in vitro. In conclusion, the anti-iNOS effect of sinomenine on EAE is mediated via the suppression of T-bet/IFN-y pathway.展开更多
Multiple sclerosis(MS)is a chronic inflammatory disease of the central nervous system(CNS)in which the immune system damages the protective insulation surrounding the nerve fibers that project from neurons.A hallmark ...Multiple sclerosis(MS)is a chronic inflammatory disease of the central nervous system(CNS)in which the immune system damages the protective insulation surrounding the nerve fibers that project from neurons.A hallmark of MS and its animal model,experimental autoimmune encephalomyelitis(EAE),is autoimmunity against proteins of the myelin sheath.Most studies in this field have focused on the roles of CD4^(+)T lymphocytes,which form part of the adaptive immune system as both mediators and regulators in disease pathogenesis.Consequently,the treatments for MS often target the inflammatory CD4^(+)T-cell responses.However,many other lymphocyte subsets contribute to the pathophysiology of MS and EAE,and these subsets include CD8^(+)T cells and B cells of the adaptive immune system,lymphocytes of the innate immune system such as natural killer cells,and subsets of innate-like T and B lymphocytes such asγδT cells,natural killer T cells,and mucosal-associated invariant T cells.Several of these lymphocyte subsets can act as mediators of CNS inflammation,whereas others exhibit immunoregulatory functions in disease.Importantly,the efficacy of some MS treatments might be mediated in part by effects on lymphocytes other than CD4^(+)T cells.Here we review the contributions of distinct subsets of lymphocytes on the pathogenesis of MS and EAE,with an emphasis on lymphocytes other than CD4^(+)T cells.A better understanding of the distinct lymphocyte subsets that contribute to the pathophysiology of MS and its experimental models will inform the development of novel therapeutic approaches.展开更多
基金supported by the International Cooperation and Exchange of the National Natural Science Foundation of China(81461138035)the National Natural Science Foundation of China(81371326,31371068,and 31571066)the National Key Research and Development Program of China(2016YFA0100802)
文摘Multiple sclerosis（MS） is a classical inflammatory demyelinating disease of the central nervous system（CNS）. Microglia are the main resident immune cells in the CNS and are closely associated with the pathogenesis of MS.In the present study, we found that mi R-30 a was highly expressed in jellyfish-like microglia in chronic active lesions of MS patients, as well as in the microglia of mice with experimental autoimmune encephalomyelitis（EAE） at the chronic phase. In vitro, the conditioned supernatant of mouse microglia overexpressing miR-30 a promoted the apoptosis of oligodendrocyte precursor cells（OPCs）, and inhibited OPC differentiation. In vivo, overexpressing miR-30 a in transplanted microglia exacerbated the progression of EAE.Overexpression and knock-down experiments in primary cultured mouse microglia showed that mi R-30 a increased the expression of IL-1 b and i NOS, which are pro-inflammatory, while inhibiting the expression of Ym-1 and CD206.Mechanistically, mi R-30 a inhibited the expression of Ppargc1 b, which is the co-activator of peroxisome proliferator-activated receptor gamma, resulting in pro-inflammatory effects. Our work shows that mi R-30 a is an important regulator of the inflammatory response in microglia, and may be a promising therapeutic target for inflammatory diseases like MS in the CNS.
基金supported by grants from the National Institutes of Health(NS094151 and NS105689)the National Multiple Sclerosis Society(RG5239-A-3)(to WL)
文摘The transcription factor nuclear factor κB（NF-κB） plays major roles in inflammatory diseases through regulation of inflammation and cell viability.Multiple sclerosis（MS） is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system（CNS）.It has been shown that NF-κB is activated in multiple cell types in the CNS of MS patients,including T cells,microglia/macrophages,astrocytes,oligodendrocytes,and neurons.Interestingly,data from animal model studies,particularly studies of experimental autoimmune encephalomyelitis,have suggested that NF-κB activation in these individual cell types has distinct effects on the development of MS.In this review,we will cover the current literature on NF-κB and the evidence for its role in the development of MS and its animal model experimental autoimmune encephalomyelitis.
文摘Multiple sclerosis is an autoimmune neurodegenerative disease of the central nervous system characterized by pronounced inflammatory infiltrates entering the brain,spinal cord and optic nerve leading to demyelination.Focal demyelination is associated with relapsing-remitting multiple sclerosis,while progressive forms of the disease show axonal degeneration and neuronal loss.The tests currently used in the clinical diagnosis and management of multiple sclerosis have limitations due to specificity and sensitivity.MicroRNAs(miRNAs)are dysregulated in many diseases and disorders including demyelinating and neuroinflammatory diseases.A review of recent studies with the experimental autoimmune encephalomyelitis animal model(mostly female mice 6–12 weeks of age)has confirmed miRNAs as biomarkers of experimental autoimmune encephalomyelitis disease and importantly at the pre-onset(asymptomatic)stage when assessed in blood plasma and urine exosomes,and spinal cord tissue.The expression of certain miRNAs was also dysregulated at the onset and peak of disease in blood plasma and urine exosomes,brain and spinal cord tissue,and at the post-peak(chronic)stage of experimental autoimmune encephalomyelitis disease in spinal cord tissue.Therapies using miRNA mimics or inhibitors were found to delay the induction and alleviate the severity of experimental autoimmune encephalomyelitis disease.Interestingly,experimental autoimmune encephalomyelitis disease severity was reduced by overexpression of miR-146a,miR-23b,miR-497,miR-26a,and miR-20b,or by suppression of miR-182,miR-181c,miR-223,miR-155,and miR-873.Further studies are warranted on determining more fully miRNA profiles in blood plasma and urine exosomes of experimental autoimmune encephalomyelitis animals since they could serve as biomarkers of asymptomatic multiple sclerosis and disease course.Additionally,studies should be performed with male mice of a similar age,and with aged male and female mice.
基金Supported by the National Natural Science Foundation(Nos.81072765,81173237 and 81273742)Beijing Natural Science Foundation(No.7142053)+2 种基金Scientific Research Key Program of Beijing Municipal Commission of Education(No.KZ201310025023)Program for Changcheng Scholars of the ImportationDevelopment of High-Caliber Talents Project of Beijing Municipal Institutions(No.CIT&TCD20140329)
文摘Objective： To study the effects of Bushen Yisui Capsule（补肾益髓胶囊, BSYSC） on the oligodendrocyte lineage genes（Olig） 1 and Olig2 in C57BL/6 mice with experimental autoimmune encephalomyelitis（EAE） in order to explore the remyelination effect of BSYSC. Methods： The mice were randomly divided into normal control（NC）, EAE model（EAE-M）, prednisone acetate（PA, 6 mg/kg）, BSYSC high-dose（3.02 g/kg） and BSYSC low-dose（1.51 g/kg） groups. The mice were induced by immunization with myelin oligodendrocyte glycoprotein（MOG） 35-55. The neurological function scores were assessed once daily. The pathological changes in mice brains were observed with hematoxylin-eosin（HE） staining and transmission electron microscope（TEM）. The protein expressions of myelin basic protein（MBP）, Olig1 and Olig2 in brains were measured by immunohistochemistry. The m RNA expressions of Olig1 and Olig 2 was also determined by quantitative real-time polymerase chain reaction. Results： Compared with the EAE-M mice,（1） the neurological function scores were significantly decreased in BSYSC-treated mice on days 22 to 40（P〈0.01）;（2） the inflammatory cells and demyelination in brains were reduced in BSYSC-treated EAE mice;（3） the protein expression of MBP was markedly increased in BSYSC-treated groups on day 18 and 40 respectively（P〈0.05 or P〈0.01）;（4） the protein expression of Olig1 was increased in BSYSC（3.02 g/kg）-treated EAE mice on day 40（P〈0.01）. Protein and m RNA expression of Olig2 was increased in BSYSC-treated EAE mice on day 18 and 40（P〈0.01）. Conclusion： The effects of BSYSC on reducing demyelination and promoting remyelination might be associated with the increase of Olig1 and Olig2.
基金supported by Science Fund of the Health Department of Jiangsu Province (No. H200504)
文摘Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating rheumatic and arthritic diseases. In our previous studies, we found that sinomenine reduced cellular infiltration within the spinal cord and alleviated experimental autoimmune encephalomyelitis （EAE） in rats. In this study, we further investigated the mechanisms of sinomenine treatment in EAE rats. In EAE rats, treatment with sinomenine exerted an anti-inducible NO synthase （anti-iNOS） effect, which is related to the reductions of Thl cytokine interferon-y （IFN-7） and its transcription factor, T-bet, in spinal cords. Moreover, sinomenine treatment of splenocytes stimulated with anti-CD3 antibody and recombinant rat in- terleukin 12 reduced the expression of T-bet and IFN-y in vitro and also reduced the capability of supernatants of splenocyte culture to induce iNOS expression by primary astrocytes. However, sinomenine had no direct inhibito- ry effect on iNOS produced by astrocytes cultured with IFN-y and tumor necrosis factor α in vitro. In conclusion, the anti-iNOS effect of sinomenine on EAE is mediated via the suppression of T-bet/IFN-y pathway.
基金The work in the researchers’lab was supported by grants from the NIH(DK104817 to L.V.K.)the Department of Defense(W81XWH-15-1-0543 to L.V.K.)+1 种基金the National Multiple Sclerosis Society(60006625 to L.V.K.)J.L.P.was supported by predoctoral NIH training grants(T32HL069765 and T32AR059039).
文摘Multiple sclerosis(MS)is a chronic inflammatory disease of the central nervous system(CNS)in which the immune system damages the protective insulation surrounding the nerve fibers that project from neurons.A hallmark of MS and its animal model,experimental autoimmune encephalomyelitis(EAE),is autoimmunity against proteins of the myelin sheath.Most studies in this field have focused on the roles of CD4^(+)T lymphocytes,which form part of the adaptive immune system as both mediators and regulators in disease pathogenesis.Consequently,the treatments for MS often target the inflammatory CD4^(+)T-cell responses.However,many other lymphocyte subsets contribute to the pathophysiology of MS and EAE,and these subsets include CD8^(+)T cells and B cells of the adaptive immune system,lymphocytes of the innate immune system such as natural killer cells,and subsets of innate-like T and B lymphocytes such asγδT cells,natural killer T cells,and mucosal-associated invariant T cells.Several of these lymphocyte subsets can act as mediators of CNS inflammation,whereas others exhibit immunoregulatory functions in disease.Importantly,the efficacy of some MS treatments might be mediated in part by effects on lymphocytes other than CD4^(+)T cells.Here we review the contributions of distinct subsets of lymphocytes on the pathogenesis of MS and EAE,with an emphasis on lymphocytes other than CD4^(+)T cells.A better understanding of the distinct lymphocyte subsets that contribute to the pathophysiology of MS and its experimental models will inform the development of novel therapeutic approaches.
