Brain macrophage development, diversity and dysregulation in health and disease

Abstract

Brain macrophages include microglia in the parenchyma, border-associated macrophages in the meningeal-choroid plexus-perivascular space, and monocyte-derived macrophages that infiltrate the brain under various disease conditions. The vast heterogeneity of these cells has been elucidated over the last decade using revolutionary multiomics technologies. As such, we can now start to define these various macrophage populations according to their ontogeny and their diverse functional programs during brain development, homeostasis and disease pathogenesis. In this review, we first outline the critical roles played by brain macrophages during development and healthy aging. We then discuss how brain macrophages might undergo reprogramming and contribute to neurodegenerative disorders, autoimmune diseases, and glioma. Finally, we speculate about the most recent and ongoing discoveries that are prompting translational attempts to leverage brain macrophages as prognostic markers or therapeutic targets for diseases that affect the brain.

Enhancing anti-EGFRvIII CAR T cell therapy against glioblastoma with a paracrine SIRPγ-derived CD47 blocker

“…To firmly differentiate MG from MdCs, we supplemented the classically used surface marker combination of CD45 int CD11b hi with the purinergic receptor P2ry12, as it has been shown to be highly specific for MG in health 56 and in the tumor context 50 . Importantly, P2ry12 has been found to be downregulated during LPS-mediated MG activation 57 and in neurodegeneration in the recently described disease-associated MG (DAM) population, which could potentially hamper our resolution of MG subpopulations 53,54 . Using conventional analysis and gating-strategy ( Fig.…”

“…The myeloid immune landscape in tumor-induced neuroinflammation harbors predominantly tissue-resident microglia (MG) and blood-borne monocyte-derived macrophages (MdCs) and dendritic cells (DCs) 50,51 . The advent of technologies that allow for high-dimensional analysis on a single cell level (scRNAseq, CyTOF, spectral FC) have added numerous flavors to MG and MdCs in health and disease [52][53][54][55] , and established surface marker combinations that better define individual immune cell populations, therefore avoiding cross-contamination leading to ambiguous conclusions. To firmly differentiate MG from MdCs, we supplemented the classically used surface marker combination of CD45 int CD11b hi with the purinergic receptor P2ry12, as it has been shown to be highly specific for MG in health 56 and in the tumor context 50 .…”

“…Multiple studies described MG subpopulations expressing CD11c (Itgax) in healthy 52 and diseased mouse brain [59][60][61] . By Seurat-based integration of six CNS-macrophage focused scRNAseq datasets, Silvin et al 54 recently incorporated the transcriptome of healthy (fetal, adult and old) and diseased MG/macrophages into one universe, termed macrophage-verse. Projection of the transcriptomic signature of CD11c + MG sampled from the corpus callosum (formerly termed "fountain of MG") of postnatal mice 59 (p7 CD11c + MG) showed strong overlap with the projected and further deconvoluted disease-associated microglia (DAM) described by Keren-Shaul 53 .…”

Influenza A virus during pregnancy disrupts maternal intestinal immunity and fetal cortical development in a dose- and time-dependent manner

“…Interestingly, the dose-dependent increased density of BAMs indicates a macrophagespecific response to IAV-induced maternal inflammation. While BAMs do not infiltrate the brain parenchyma to interact with early neuronal cells like microglia do, they are in direct contact with the periphery and thus play a critical role in immune defense [77,100]. At least one study demonstrates that poly I:C-induced MIA directly impacts the homeostatic function of embryonic brain macrophages, leading to increases in ChP macrophage populations [26].…”

Dynamic changes in mitochondria support phenotypic flexibility of microglia

“…An essential and defining characteristic of microglia is their ability to rapidly remodel their attributes and shift into different functional states (1)(2)(3). During embryonic and early postnatal development, microglia undergo extensive morphological and transcriptomic changes as they support different phases of CNS maturation (4)(5)(6)(7)(8)(9). In adulthood, microglia exhibit prominent regional differences in cell density, morphology, motility, and phagocytic behaviors to optimally support local neuron function and tissue homeostasis (10)(11)(12)(13)(14)(15).…”