Innate immunity in the central nervous system (CNS) comprises resident microglia, perivascular and meningeal macrophages, as well as blood-derived monocytes/macrophages. The differential roles of these heterogenous myeloid cell populations in neuropsychiatric disorders are increasingly recognized. The recruitment of monocytes into the CNS can exacerbate neuroinflammation, and trigger neuron injury or death. On the other hand, the integration of peripherally derived myeloid cells into the pool of CNS phagocytes can also contribute to the resolution of CNS inflammation. We recently discovered that the adoptive transfer of the monocyte/macrophage progenitors attenuates disease in mouse models of Alzheimer´s disease (AD) and amyotrophic lateral sclerosis (ALS). We also identified human progenitors that efficiently target the damaged CNS. In this study, we shall evaluate the therapeutic potential of the human monocyte/macrophage progenitors in mouse models of AD, ALS and multiple sclerosis. We shall use genetic lineage tracing, flow and mass cytometry, as well as transcriptomic analysis to investigate the differentiation and functional activation of human-derived cells in a tissue-specific manner. In addition, using mass cytometry and transcriptomic analysis, we shall assess the phenotypic and transcriptional changes of peripherally derived monocytes/macrophages in patients with neuropsychiatric disorders, and expose monocytes/macrophages to CNS environment (e.g. cerebrospinal fluid). The project aims to provide preclinical evidence for the use of monocyte/macrophage progenitors in the treatment of neuropsychiatric disorders. The experiments will contribute to a better understanding of regulatory or cytotoxic effects of monocytes/macrophages in neuropathological conditions.