The continuum of microglial subpopulations to functional changes in multiple sclerosis

Upon disruption of brain homeostasis, microglia typically undergo a set of changes in their protein expression, morphology, metabolism and proliferation. Using mass cytometry (CyTOF) and imaging CyTOF (IMC), we showed phenotypic heterogeneity of macrophage/microglia in active lesions of progressive multiple sclerosis (PMS), ranging from protective to activated events including increase in phagocytic phenotype and expression of pro-inflammatory molecules which can lead to sustained neuroinflammation and eventually further contribute to neurodegeneration. However, it remains to be investigated whether this phenotypic heterogeneity correlates with diversity of local drivers or microglial functions towards pathological site.

Here, we aim to map the continuum of microglial phenotypes to functional/metabolomic changes in different lesion types of MS and shadow plaques. Brain tissues from donors without neuropathology and those with non-MS neuroinflammation will be used as controls. We will employ two state-of-the-art spatial technologies, which are IMC and DESI-ion mobility-TOF mass spectrometry for in situ analysis of metabolites and lipids. The relationships between phenotypic, metabolomic and functional changes of microglia/macrophage in different lesion types compared to normal appearing white (NAWM) and grey matter (NAGM) as well as controls will be deciphered. Cell-cell interaction between different microglial/macrophage subsets and other CNS cells will also be evaluated. Finally, the findings will be validated/compared with the relapsing-remitting EAE mouse model.

Our findings will provide new insights into the roles of microglia/macrophage and their responses to local cues in different lesion types towards MS neuropathological sites, which will lead to better understanding biology of human microglia and their roles in different MS stages. Furthermore, the results that will be obtained from the area with remyelination will additionally provide evidence for the role of microglia in regeneration process of MS, which will have an important impact on a future development of the treatment targeting microglia.