Microglia and monocyte-derived macrophage dynamics during multiple sclerosis lesion evolution

• Applicants: Dr. Stefan Nessler; Professorin Dr. Christine Stadelmann-Nessler
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 435430032

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS characterized by demyelination and axonal loss. The immune cell infiltrates involved in demyelination consist of T lymphocytes and macrophages. The macrophages, which strip and phagocytose myelin, can either be of microglia origin or derived from extravasated monocytes (monocyte-derived macrophages, MDM).The relative contribution of microglia and MDM to lesion pathogenesis, tissue damage and thus disability in MS is poorly characterized. Thus, the overall goal of this proposal is to define the origin and function of macrophages during MS lesion evolution. Based on our previous and preliminary data, we hypothesize that the origin and pathogenetic potential of the predominant macrophage population changes during MS lesion evolution. In prephagocytic MS lesions, macrophages are most likely of microglia origin, whereas MDMs are the dominant effector cells in acutely demyelinating MS lesions. Macrophages in chronic MS lesions may be mainly microglia-derived.In Aim 1, we will use recently characterized microglia and MDM marker proteins to clarify the origin of macrophages in different MS lesion stages. These results in human tissue will be corroborated in demyelinating animal models using reporter mice and depletion experiments. Aim 2 will test how particular macrophage subsets are induced. Aim 3 will then reveal the functional properties of particular macrophages and track their long-term destiny by fate-mapping. Aim 4 will clarify whether MS lesions resolve due to macrophage cell death or emigration.In summary, the overarching goal of this proposal is to gain further insight into macrophage dynamics, their ontogenic origin and their effector functions in MS and relevant experimental models. The proposal will provide new insights for designing disease stage-dependent treatment strategies.

• DFG Programme: Research Grants