A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment

Hove, Hannah Van; Martens, Liesbet; Scheyltjens, Isabelle; Vlaminck, Karen De; Antunes, Ana Rita Pombo; Prijck, Sofie De; Vandamme, Niels; Schepper, Sebastiaan De; Isterdael, Gert Van; Scott, Charlotte; Aerts, Jeroen; Berx, Geert; Boeckxstaens, Guy E.; Vandenbroucke, Roosmarijn E.; Vereecke, Lars; Moechars, Diederik; Guilliams, Martin; Ginderachter, Jo A. Van; Saeys, Yvan; Movahedi, Kiavash

doi:10.1038/s41593-019-0393-4

Cited by 685 publications

(963 citation statements)

References 79 publications

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“…In the choroid plexus, P2ry12-CreER recombination marked a small number of IBA1 + cells, as well as a small number of IBA1-negative or IBA1-low cells, unlike Cx3cr1-CreER, which showed recombination in most choroid plexus IBA1 + macrophages ( Figure 1G). Some of the P2ry12-CreER; Ai14 recombined cells appeared to be on the surface of the choroid plexus, consistent with a recently published study that revealed a microglia-like, P2ry12-expressing "CP-epi" subpopulation of choroid plexus macrophages, which may be Kolmer's epiplexus cells (Ling et al, 1998;Van Hove et al, 2019).…”

Section: P2ry12-creer-mediated Recombination Efficiently and Specificsupporting

confidence: 89%

New Tools for Genetically Targeting Myeloid Populations in the Central Nervous System

Gl¹,

Lizama²,

Ae³

et al. 2019

Preprint

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As the resident macrophages of the brain and spinal cord, microglia are crucial for the phagocytosis of infectious agents, apoptotic cells and synapses. Developmentally, microglia originate from the embryonic yolk sac and serve important roles in the sculpting of neonatal neural circuits. During brain injury or infection, bone-marrow derived macrophages invade neural tissue, making it difficult to distinguish between invading macrophages and resident microglia. In addition to circulation-derived monocytes, other non-microglial central nervous system (CNS) macrophage subtypes include borderzone (meningeal and perivascular) and choroid plexus macrophages. To distinguish between resident microglia and these other CNS macrophage subtypes, we generated a P2ry12-CreER mouse line. P2RY12 is a microglialspecific nucleotide sensing GPCR that is important for microglial response to tissue damage. Using immunofluorescent labeling and flow cytometry experiments, we show that P2ry12-CreER recombination is exceptionally specific to parenchymal microglia. We also perform ribosome immunoprecipitations and transcriptional profiling of P2ry12-CreER recombined cells, using a Cre-dependent Rpl22-HA mouse line. By identifying genes enriched in this dataset that are not correspondingly enriched in a broader Cx3CR1-CreER; Rpl22 dataset, we isolate a number of borderzone macrophage-specific transcripts, including the gene PF4. Using a PF4-Cre mouse line, we show that PF4 expression robustly marks borderzone macrophages. Together, we demonstrate two new methods to genetically target distinct CNS macrophage subtypes.

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Section: P2ry12-creer-mediated Recombination Efficiently and Specificsupporting

confidence: 89%

New Tools for Genetically Targeting Myeloid Populations in the Central Nervous System

Gl¹,

Lizama²,

Ae³

et al. 2019

Preprint

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“…2B). Furthermore, monocytes are short‐lived cells, while all the macrophage populations at least partially self‐renew from an internal pool . We did not observe tamoxifen‐independent Zsgreen expression in blood monocytes from Cx3cr1 CreERT2 :R26‐CAG‐Zsgreen mice (Fig.…”

mentioning

confidence: 72%

Identifying the variables that drive tamoxifen‐independent CreERT2 recombination: Implications for microglial fate mapping and gene deletions

et al. 2019

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Ligand‐dependent Cre recombinases such as the CreERT2 system allow for tamoxifen‐inducible Cre recombination. Important examples are the Cx3cr1‐CreERT2 and Sall1‐CreERT2 lines that are widely used for fate mapping and gene deletion studies of brain macrophages. Our results now show that both CreERT2 lines can exhibit a high rate of tamoxifen‐independent “leaky” excision with some reporter strains, while this is not observed with others. We suggest that this disparity is determined by the length of the floxed transcriptional STOP cassette that is incorporated in the various reporter lines. In addition, the rate of spontaneous recombination was also determined by the CreERT2 expression levels and the longevity of the CreERT2‐expressing cells. The implications of these results are discussed in the context of fate mapping and inducible gene deletion studies in macrophages and microglia.

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“…Five independent, publicly available, murine RNA‐sequencing datasets were used to compare with our human datasets (Bowman et al, ; Heng et al, ; Pluvinage et al, ; Qian et al, ; Van Hove et al, ). Differential gene expression analysis was completed with edgeR package (Robinson, McCarthy, & Smyth, ).…”

Section: Methodsmentioning

confidence: 99%

Species differences in immune‐mediated CNS tissue injury and repair: A (neuro)inflammatory topic

Healy

Yaqubi

Ludwin

et al. 2019

Glia

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Cells of the adaptive and innate immune systems in the brain parenchyma and in the meningeal spaces contribute to physiologic functions and disease states in the central nervous system (CNS). Animal studies have demonstrated the involvement of immune constituents, along with major histocompatibility complex (MHC) molecules, in neural development and rare genetic disorders (e.g., colony stimulating factor 1 receptor [CSF1R] deficiency). Genome wide association studies suggest a comparable role of the immune system in humans. Although the CNS can be the target of primary autoimmune disorders, no current experimental model captures all of the features of the most common human disorder placed in this category, multiple sclerosis (MS). Such features include spontaneous onset, environmental contributions, and a recurrent/progressive disease course in a genetically predisposed host. Numerous therapeutic interventions related to antigen and cytokine specific therapies have demonstrated effectiveness in experimental autoimmune encephalomyelitis (EAE), the animal model used to define principles underlying immune‐mediated mechanisms in MS. Despite the similarities in the two diseases, most treatments used to ameliorate EAE have failed to translate to the human disease. As directly demonstrated in animal models and implicated by correlative studies in humans, adaptive and innate immune constituents within the systemic compartment and resident in the CNS contribute to the disease course of neurodegenerative and neurobehavioral disorders. The expanding knowledge of the molecular properties of glial cells provides increasing insights into species related variables. These variables affect glial bidirectional interactions with the immune system as well as their own production of “immune molecules” that mediate tissue injury and repair.

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A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment

Cited by 685 publications

References 79 publications

New Tools for Genetically Targeting Myeloid Populations in the Central Nervous System

New Tools for Genetically Targeting Myeloid Populations in the Central Nervous System

Identifying the variables that drive tamoxifen‐independent CreERT2 recombination: Implications for microglial fate mapping and gene deletions

Species differences in immune‐mediated CNS tissue injury and repair: A (neuro)inflammatory topic

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