Neuroprotective effects of vascular endothelial growth factor A in the experimental autoimmune encephalomyelitis model of multiple sclerosis

Multiple sclerosis（MS）is a chronic inflammatory disease of the central nervous system（CNS）,characterized by multiple demyelinating plaques in the white matter.For decades,the focus of MS research has been on inflammation-mediated demyelination of the white matter.

Oligodendrocyte ablation as a tool to study demyelinating diseases

Multiple sclerosis（MS） is an autoimmune mediated neurodegenerative disease characterized by demyelination and oligodendrocyte（OL） loss in the central nervous system and accompanied by local inflammation and infiltration of peripheral immune cells. Although many risk factors and symptoms have been identified in MS, the pathology is complicated and the cause remains unknown. It is also unclear whether OL apoptosis precedes the inflammation or whether the local inflammation is the cause of OL death and demyelination. This review briefly discusses several models that have been developed to specifically ablate oligodendrocytes in an effort to separate the effects of demyelination from inflammation.

MiR-30a Positively Regulates the Inflammatory Response of Microglia in Experimental Autoimmune Encephalomyelitis

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.

Bel 10 is required for the development and suppressive function of Foxp3^(+)regulatory T cells

Foxp3^(+)regulatory T(Treg)cells play a critical role in peripheral tolerance.Bcl1O,acting as a scaffolding protein in the Carma1-Bcl10-Malt1(CBM)complex,has a critical role in TCR-induced signaling,leading to NF-kB activation and is required for T-cell activation.The role of Bcl1O in conventional T(Tconv)cells has been well characterized;however,the role of Bcl1 in the development of Treg cells and the maintenance of the suppressive function and identity of these cells has not been well characterized.In this study,we found that Bcl10 was required for not only the development but also the function of Treg cells.After deleting Bcl1O in T cells,we found that the development of Treg cells was significantly impaired.When Bcl1O was specifically deleted in mature Treg cells,the suppressive function of the Treg cells was impaired,leading to lethal autoimmunity in Bcl10^(fl/fl)Foxp3^(cre) mice.Consistently,in contrast to WT Treg cells,Bcl10-deficient Treg cells could not protect Rag1-deficient mice from T-cell transfer-induced colitis.Furthermore,Bcl1O-deficient Treg cells downregulated the expression of a series of Treg-cell effector and suppressive genes and decreased effector Treg-cell populations.Moreover,Bcl1O-deficient Treg cells were converted into IFNγ-producing proinflammatory cells with increased expression of the transcription factors T-bet and HIF-1α.Together,our study results provide genetic evidence,indicating that Bcl1O is required for the development and function of Treg cells.