CNS Border-Associated Macrophages: Ontogeny and Potential Implication in Disease

Abstract

Being immune privileged, the central nervous system (CNS) is constituted by unique parenchymal and non-parenchymal tissue-resident macrophages, namely, microglia and border-associated macrophages (BAMs), respectively. BAMs are found in the choroid plexus, meningeal and perivascular spaces, playing critical roles in maintaining CNS homeostasis while being phenotypically and functionally distinct from microglial cells. Although the ontogeny of microglia has been largely determined, BAMs need comparable scrutiny as they have been recently discovered and have not been thoroughly explored. Newly developed techniques have transformed our understanding of BAMs, revealing their cellular heterogeneity and diversity. Recent data showed that BAMs also originate from yolk sac progenitors instead of bone marrow-derived monocytes, highlighting the absolute need to further investigate their repopulation pattern in adult CNS. Shedding light on the molecular cues and drivers orchestrating BAM generation is essential for delineating their cellular identity. BAMs are receiving more attention since they are gradually incorporated into neurodegenerative and neuroinflammatory disease evaluations. The present review provides insights towards the current understanding regarding the ontogeny of BAMs and their involvement in CNS diseases, paving their way into targeted therapeutic strategies and precision medicine.

Keywords: CNS border-associated macrophages; development; disease; molecular cues; origin; tissue-resident macrophages; yolk sac.

Figure 1

BAM origin and propagation in the developing mouse brain. The early differentiation of macrophage progenitors is regulated by the expression of RUNX1, PU.1, and IRF8 in the yolk sac, where the primitive erythro-myeloid progenitors (EMPs) give rise to CD45⁺ c-kit^lo CX₃CR1⁻ immature (A1) cells and subsequently to CD45⁺ c-kit⁻ CX₃CR1⁺ (A2) cells. In the presence of TGF-β, A2 cells initiate a microgliogenesis program upon settlement in the brain parenchyma. In the absence of the TGF-β, A2 cells do not enter the brain parenchyma, populate the abutting connective tissue, and may follow distinct developmental pathways: (1) IGF1R, IRF8, ITGB1, and MAFB restrict progenitors to the meninges, either dura or the subdural mesenchymal niche; (2) IGF1R, IRF8, and CSF1R dictate progenitors’ residency within the choroid plexus; (3) ITGB1, IGF1R, c-MAF, MAFB, IRF8, TLN1, and NOTCH3 stimulate pvΜΦ generation postnatally from sdΜΦ. However, it is not yet fully understood if the dmΜΦ share common progenitors and drivers with sdΜΦ during embryogenesis. dmΜΦ: dural macrophages; sdΜΦ: subdural macrophages; pvΜΦ: perivascular macrophages; cpΜΦ: stromal choroid plexus macrophages; cp^epiΜΦ: choroid epiplexus macrophages; BBB: blood–brain barrier.