038 – Soluble TNF inhibits phagocytosis of myelin debris by mouse macrophage and microglia, and remyelination of demyelinated lesions
Athina Boutou (1) – Maria Karamita (1) – Vasiliki Kyrargyri (1) – David Szymkowski (2) – Christopher Barnum (3) – Raymond Tesi (3) – Lesley Probert (1)
Hellenic Pasteur Institute, Labortatory of Molecular Genetics, Department of Immunology, Athens, Greece (1) – Xencor Inc, Xencor, Monrovia, California, United States (2) – INmune Bio, INmune Bio, La Jolla, California, United States (3)
Remyelination is a spontaneous regenerative process of the adult CNS that mainly fails in multiple sclerosis. The transmembrane form of TNF (tmTNF) and TNFR2 are critical for remyelination while soluble TNF (solTNF) has opposing inhibitory effect on remyelination. Using the cuprizone demyelination remyelination model, s.c. administration of a selective inhibitor of solTNF named XPro1595 that crosses the intact blood-brain barrier in pharmacological concentrations, did not prevent toxin-induced demyelination, but permitted profound early remyelination and prevented disease-associated neurodegeneration and decline in motor performance. Remyelination in the XPro1595-treated mice was associated with higher proportions of large foamy macrophages containing PLP-immunoreactive myelin degradation products and improved clearance of myelin debris in lesions compared to controls, suggesting that Xpro1595 enhances remyelination by increasing phagocytosis of myelin debris by CNS macrophages. To further investigate this, we set-up an in vitro myelin phagocytosis assay. RAW 264.7 macrophage cells, adult mouse peritoneal macrophages, and neonatal mouse microglia were cultured with myelin in the absence or presence of XPro1595 (100 ng/ml). XPro1595 significantly increased the amount of myelin phagocytosis, as measured by increased numbers of MBP-immunoreactive cells. These results confirm that solTNF inhibits the pro-repair potential of macrophages to phagocytose myelin debris and that this effect is cell autonomous. The in vitro myelin phagocytosis assay is a useful tool for investigating the molecular mechanisms of functional phenotype switching in macrophages, for identifying additional therapeutic targets to increase remyelination and for testing the differential contributions of microglia and peripheral macrophages in lesions. Together, our results suggest that selective inhibition of solTNF by brain-penetrating agents such as XPro1595 promotes remyelination by increasing the presence of pro-repair over pro-inflammatory macrophages, and represents a promising approach for achieving neuroprotection in progressive MS.