Several lines of evidence suggest that the innate immune system plays a critical role in the induction and regulation of adaptive autoimmune responses in MS, as well as in myelin and axonal damage within the CNS. Cells of the innate immune system include dendritic cells, macrophages and microglia. Relevance of these cells to MS relate to their functions as antigen presenting cells, producers of cytokines/chemokines, in the clearance of debris within the CNS and perhaps perpetrators of damage to myelin and/or axons. In particular, we are studying the role of Triggering Receptor Expressed on Myeloid cells-2 (TREM-2) expressed on innate immune cells in MS tissue and the EAE model. TREM-2 is emerging as an important negative regulator of inflammation. These studies are funded by the National Multiple Sclerosis Society (NMSS) and the Federazione Italiana Sclerosi Multipla (FISM). An important tool we are using to investigate the roles of innate immune cells in EAE is CNS imaging in vivo and ex vivo using two-photon microscopy.