Origin, fate and dynamics of macrophages at central nervous system interfaces

Abstract

Perivascular, meningeal and choroid plexus macrophages are non-parenchymal macrophages that mediate immune responses at brain boundaries. Although the origin of parenchymal microglia has recently been elucidated, much less is known about the precursors, the underlying transcriptional program and the dynamics of the other macrophages in the central nervous system (CNS). It has been assumed that they have a high turnover with blood-borne monocytes. However, large scale single-cell RNA-sequencing reveals a striking molecular overlap between perivascular macrophages and microglia but not monocytes. Using several fate mapping approaches and parabiosis we demonstrate that CNS macrophages arise from yolk sac precursors during embryonic development and remain a stable population. Notably, the generation of CNS macrophages relies on the transcription factor Pu.1 whereas myb, Batf3 and Nr4a1 are not required. Upon autoimmune inflammation, macrophages undergo extensive self-renewal by local proliferation. Our data provide challenging new insights into brains innate immune system.

Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension

“…First, we used well-established criteria to identify brain PVMs (18). Brain PVMs were identified as myeloid cells closely associated with the abluminal side of cerebral blood vessels and (a) expressing the mannose receptor CD206 (Figure 1 Figure 1D); (c) expressing low levels of IBA1, compared with microglial cells ( Figure 1C); and (d) endowed of phagocytic activity assessed by injection of dextran into the lateral ventricles ( Figure 1, B-D, and ref.…”

“…Perivascular macrophages (PVMs) and meningeal and choroid plexus macrophages represent the bulk of resident brain macrophages (18), and are distinct from macrophages infiltrating the wall of large vessels in inflammatory conditions, such as atherosclerosis (19). Residing in the intracerebral perivascular space, delimited by the glia limitans and the vascular basement membrane (Virchow-Robin space), PVMs are closely apposed to the outer vessel wall and originate from hematopoietic precursors (18,20,21).…”

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…These cells have a dual origin: some derive from the myeloid progenitors generated by the yolk sac in the earliest stages of embryogenesis. In addition, a continuous replacement is observed by cells from the bloodstream [52] or from stromal progenitors [100]. Thus, macrophagic cells of the choroid plexus stroma differ from meningeal macrophages, macrophages of the perivascular spaces and microglia which are stable resident populations.…”

“…Subarachnoid macrophages exert scavenger functions and present CNS antigens to T cells entering this CSF space as shown by elegant in vivo live cell imaging studies [8,84,107]. Combined parabiosis and fate-mapping studies in transgenic mice provided recent evidence that subarachnoid macrophages arise from hematopoietic precursors during embryonic development and establish a stable long-lived population of innate immune cells in this compartment [52]. These myeloid cells share this origin with the Kolmer's epiplexus cells that reside on the apical-i.e.…”

Microglia in steady state

“…However, the yolk sac EMPs and embryonic microglia are independent of the transcription factor c-myb, which is a key transcription factor for the maintenance of hematopoietic stem cells (HSCs) derived from embryonic definitive hematopoiesis microglia as well as perivascular and meningeal macrophages in the CNS. It is also well accepted that adult microglia are derived from a single wave of yolk sac EMPs, with no further contribution of myeloid progenitors from another hematopoietic origin, such as circulating HSC-derived myeloid progenitors from adult bone marrow (20,21,(23)(24)(25)(26)(27). Upon entering the developing neuroectoderm, the embryonic microglial population expands via proliferation throughout development (21,22,28).…”