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Microglia are tissue-resident macrophages implicated in central nervous system (CNS) development, homeostasis, and response to injury. Recent advances in transcriptomics, multiplex protein expression analysis, and experimental depletion of microglia have cemented their importance. However, it is still unclear which models are best suited to investigate microglia and explore their function in human disease. Here, we discuss issues regarding off-targeting during experimental manipulation, and differences and similarities between human and rodent microglia. With new developments in transgenic lines and human-rodent chimeras, we anticipate that in coming years, a clearer picture of microglia function in health and disease will emerge., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The proliferation, differentiation and survival of mononuclear phagocytes depend on signals from the receptor for macrophage colony-stimulating factor, CSF1R. The mammalian Csf1r locus contains a highly conserved super-enhancer, the fms-intronic regulatory element (FIRE). Here we show that genomic deletion of FIRE in mice selectively impacts CSF1R expression and tissue macrophage development in specific tissues. Deletion of FIRE ablates macrophage development from murine embryonic stem cells. Csf1r ΔFIRE/ΔFIRE mice lack macrophages in the embryo, brain microglia and resident macrophages in the skin, kidney, heart and peritoneum. The homeostasis of other macrophage populations and monocytes is unaffected, but monocytes and their progenitors in bone marrow lack surface CSF1R. Finally, Csf1r ΔFIRE/ΔFIRE mice are healthy and fertile without the growth, neurological or developmental abnormalities reported in Csf1r -/- rodents. Csf1r ΔFIRE/ΔFIRE mice thus provide a model to explore the homeostatic, physiological and immunological functions of tissue-specific macrophage populations in adult animals.

Central nervous system (CNS) injury incurs a rapid innate immune response, including that from macrophages derived from endogenous microglia and circulating monocytes infiltrating the lesion site. One example of such injury is the demyelination observed in the autoimmune disease multiple sclerosis (MS), where macrophages are implicated in both myelin injury and regeneration. Although initially microglia and monocyte-derived macrophages were considered to have identical origins, gene expression, and function, recent advances have revealed important distinctions in all three categories and have caused a paradigm shift in view of their unique identity and roles. This has important consequences for understanding their individual contribution to neurological function and therapeutic targeting of these populations in diseases like MS. Here, we address the differences between CNS endogenous and exogenously-derived macrophages with a particular focus on myelin damage and regeneration., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Microglia are the resident macrophages of the central nervous system that survey the microenvironment for signals of injury or infection. The response to such signals induces an inflammatory response involving macrophages derived from both resident microglia and recruited circulating monocytes. Although implicated as contributors to autoimmune-mediated injury, microglia/ macrophages have recently been shown to be critical for the important central nervous system regenerative process of remyelination. This functional dichotomy may reflect their ability to be polarized along a continuum of activation states including the well-characterized cytotoxic M1 and regenerative M2 phenotypes. Here, we review the roles of microglia, monocytes and the macrophages which they give rise to in creating lesion environments favourable to remyelination, highlighting the specific roles of M1 and M2 phenotypes and how the pro-regenerative role of the innate immune system is altered by ageing. Here, we review the roles of microglia, monocytes and the macrophages, which they give rise to in creating lesion environments favourable to remyelination, highlighting the specific roles of activation phenotypes and how the pro-regenerative role of the innate immune system is altered by ageing., (© 2014 International Society for Neurochemistry.)

The lack of therapies for progressive multiple sclerosis highlights the need to understand the regenerative process of remyelination that can follow CNS demyelination. This involves an innate immune response consisting of microglia and macrophages, which can be polarized to distinct functional phenotypes: pro-inflammatory (M1) and anti-inflammatory or immunoregulatory (M2). We found that a switch from an M1- to an M2-dominant response occurred in microglia and peripherally derived macrophages as remyelination started. Oligodendrocyte differentiation was enhanced in vitro with M2 cell conditioned media and impaired in vivo following intra-lesional M2 cell depletion. M2 cell densities were increased in lesions of aged mice in which remyelination was enhanced by parabiotic coupling to a younger mouse and in multiple sclerosis lesions that normally show remyelination. Blocking M2 cell-derived activin-A inhibited oligodendrocyte differentiation during remyelination in cerebellar slice cultures. Thus, our results indicate that M2 cell polarization is essential for efficient remyelination and identify activin-A as a therapeutic target for CNS regeneration.