Microglia play a key role in the initiation and perpetuation of de- and remyelination because of their ability to present antigens and clear cell debris by phagocytosis. Different factors expressed or secreted by microglia seem to play an important role in regenerative processes. But it remains unclear which factors lead to a protective microglial phenotype and recent data indicate region-specific differences within the central nervous system (CNS) for both de-/remyelination and microglial response. In order to identify important factors that promote neuroprotection, we examined changes in microglial phenotypes in the cuprizone model. We undertook an extensive and detailed analysis of the expression of surface markers as well as cytokines, growth factors, and the phagocytosis activity of microglia. We found a pronounced increase of phagocytosis activity of microglia during demyelination associated with an upregulation of phagocytic receptors, from which TREM-2b was the most prominent. The expression of MHC II was only increased at the peak of demyelination but costimulatory molecules showed no significant changes. Interestingly, the proinflammatory cytokine TNF-α was upregulated while the anti-inflammatory cytokines IL-10 and TGF-ß remained unchanged. The growth factors IFG-1 and FGF-2, which were both suggested to promote remyelination, were increased during demyelination. Our findings characterise changes of microglial markers during de- and remyelination indicating that debris clearance mediated via TREM-2b plays a central role in the regulation of these processes. Microglial phagocytosis as well as production of TNF-α, IGF-1, and FGF-2 seems to be important factors for the creation of an environment promoting regeneration.