Immovable Object Meets Unstoppable Force? Dialogue Between Resident and Peripheral Myeloid Cells in the Inflamed Brain

Inflammation of the brain parenchyma is characteristic of neurodegenerative, autoimmune, and neuroinflammatory diseases. During this process, microglia, which populate the embryonic brain and become a permanent sentinel myeloid population, are inexorably joined by peripherally derived monocytes, recruited by the central nervous system. These cells can quickly adopt a morphology and immunophenotype similar to microglia. Both microglia and monocytes have been implicated in inducing, enhancing, and/or maintaining immune-mediated pathology and thus disease progression in a number of neuropathologies. For many years, experimental and analytical systems have failed to differentiate resident microglia from peripherally derived myeloid cells accurately. This has impeded our understanding of their precise functions in, and contributions to, these diseases, and hampered the development of novel treatments that could target specific cell subsets. Over the past decade, microglia have been investigated more intensively in the context of neuroimmunological research, fostering the development of more precise experimental systems. In light of our rapidly growing understanding of these cells, we discuss the differential origins of microglia and peripherally derived myeloid cells in the inflamed brain, with an analysis of the problems resolving these cell types phenotypically and morphologically, and highlight recent developments enabling more precise identification.