We had a farewell lunch for Natacha at Keren Restaurant in Dupont Circle. The food is REALLY delicious. Natacha will be leaving us to start medical school in the Fall. Congratulations and good luck!
Creatine enhances mitochondrial-mediated oligodendrocyte survival following demyelinating injury
Chamberlain KA, Chapey KS, Nanescu SE, Huang JK
Chronic oligodendrocyte loss, which occurs in the demyelinating disorder multiple sclerosis (MS), contributes to axonal dysfunction and neurodegeneration. Current therapies are able to reduce MS severity, but do not prevent transition into the progressive phase of the disease, which is characterized by chronic neurodegeneration. Therefore, pharmacological compounds that promote oligodendrocyte survival could be beneficial for neuroprotection in MS. Here, we investigated the role of creatine, an organic acid involved in ATP buffering, in oligodendrocyte function. We found that creatine directly increased mitochondrial ATP production in oligodendrocyte lineage cell cultures, and exerted robust protection on oligodendrocytes by preventing cell death in both naïve and lipopolysaccharide (LPS)-treated mixed glia. Moreover, lysolecithin-mediated demyelination in mice deficient in the creatine-synthesizing enzyme guanidinoacetate-methyltransferase (Gamt) did not affect oligodendrocyte precursor cell (OPC) recruitment, but resulted in exacerbated apoptosis of regenerated oligodendrocytes in CNS lesions. Remarkably, creatine administration into Gamt deficient and wild-type mice with demyelinating injury reduced oligodendrocyte apoptosis, thereby increasing oligodendrocyte density and myelin basic protein (MBP) staining in CNS lesions. We found that creatine did not affect the recruitment of macrophages/microglia into lesions, suggesting that creatine affects oligodendrocyte survival independently of inflammation. Together, our results demonstrate a novel function for creatine in promoting oligodendrocyte viability during CNS remyelination.
We're excited to have received the first Roger D. Semerad Award for Research in the Neurosciences from @TurnFirstMS! The funds will be used in collaboration with the Georgetown MS Clinic for Stephanie to pursue her project on investigating the role of IL4I1 in MS clinical samples. Link to the annoucement below:
We had our end of the year lunch at Zannchi in Georgetown. We also bade farewell to Kelly, who will be starting her postdoc at the NIH in 2017.
IL4I1 augments CNS remyelination and axonal protection by modulating T cell driven inflammation
Psachoulia K, Chamberlain KA, Heo D, Davis SE, Paskus JD, Nanescu SE, Dupree JL, Wynn TA, Huang JK
Myelin regeneration (remyelination) is a spontaneous process that occurs following central nervous system demyelination. However, for reasons that remain poorly understood, remyelination fails in the progressive phase of multiple sclerosis. Emerging evidence indicates that alternatively activated macrophages in central nervous system lesions are required for oligodendrocyte progenitor differentiation into remyelinating oligodendrocytes. Here, we show that an alternatively activated macrophage secreted enzyme, interleukin-four induced one (IL4I1), is upregulated at the onset of inflammation resolution and remyelination in mouse central nervous system lesions after lysolecithin-induced focal demyelination. Focal demyelination in mice lacking IL4I1 or interleukin 4 receptor alpha (IL4Rα) results in increased proinflammatory macrophage density, remyelination impairment, and axonal injury in central nervous system lesions. Conversely, recombinant IL4I1 administration into central nervous system lesions reduces proinflammatory macrophage density, enhances remyelination, and rescues remyelination impairment in IL4Rα deficient mice. We find that IL4I1 does not directly affect oligodendrocyte differentiation, but modulates inflammation by reducing interferon gamma and IL17 expression in lesioned central nervous system tissues, and in activated T cells from splenocyte cultures. Remarkably, intravenous injection of IL4I1 into mice with experimental autoimmune encephalomyelitis at disease onset significantly reversed disease severity, resulting in recovery from hindlimb paralysis. Analysis of post-mortem tissues reveals reduced axonal dystrophy in spinal cord, and decreased CD4+ T cell populations in spinal cord and spleen tissues. These results indicate that IL4I1 modulates inflammation by regulating T cell expansion, thereby permitting the formation of a favourable environment in the central nervous system tissue for remyelination. Therefore, IL4I1 is a potentially novel therapeutic for promoting central nervous system repair in multiple sclerosis.
Alisha has received a Fulbright Scholarship and will be attending University College London in the Fall! Congratulations!!!
We had our end of the year lunch at El Centro in Georgetown this year. It was also Nada's last week in the lab as she will be moving on to a new job after the new year!
We're excited to announce that the National Institutes of Health has funded our R21 grant application! This grant will provide funds for our study on the role of inflammation in CNS remyelination for the next two years.