Cxcr4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke

Werner, Yves; Mass, Elvira; Kumar, Praveen Ashok; Ulas, Thomas; Händler, Kristian; Horne, Arik; Klee, Kathrin; Lupp, Amelie; Schütz, Dagmar; Saaber, Friederike; Redecker, Christoph; Schultze, Joachim L.; Geissmann, Frédéric; Stumm, Ralf

doi:10.1038/s41593-020-0585-y

Cited by 147 publications

(186 citation statements)

References 63 publications

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“…Likewise, while Williams et al have identified MAC-AIR as self-renewing resident macrophages seeded by monocytes during the perinatal period (15), the ontogeny of Trem2 hi -Slamf9 and Trem2 hi -Gpnmb macrophages requires further investigation. However, extrapolation of decades of research on foamy macrophage accumulation in atherosclerosis clearly suggests a monocytic origin of these cells,which could be confirmed in future analyses using recently developed monocyte fate-mapping models based on Ms4a3(57) or Cxcr4(58). Finally, whether similar subpopulations of foamy/Trem2 hi macrophages can be detected in human lesions will require sampling of a larger number of human lesional macrophages.…”

mentioning

confidence: 83%

Integrated scRNA-seq analysis identifies conserved transcriptomic features of mononuclear phagocytes in mouse and human atherosclerosis

Zernecke

Erhard

Weinberger

et al. 2020

Preprint

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RationaleAccumulation of mononuclear phagocytes (monocytes, macrophages and dendritic cells) in the vessel wall is a hallmark of atherosclerosis. Although single-cell RNA-sequencing (scRNA-seq) has shed new light on immune cell transcriptional diversity in atherosclerosis, it is still unknown whether the transcriptional states of mononuclear phagocytes are conserved between mouse and human atherosclerosis.ObjectiveTo integrate and compare macrophage and dendritic cell transcriptomes in mouse and human atherosclerosis.Methods and resultsWe integrated 12 scRNA-seq datasets of immune cells isolated from healthy or atherosclerotic mouse aortas, and scRNA-seq data from 11 patients (n=4 coronary vessels, n=7 carotid endarterectomy specimens) from two independent studies. Integration of mouse data recovered previously described macrophage populations and identified novel subpopulations with discrete transcriptomic signatures within populations of aortic resident (Lyve1), inflammatory (Il1b), as well as foamy (Trem2hi) macrophages. We identified unique transcriptomic features distinguishing aortic intimal resident macrophages from atherosclerosis-associated Trem2hi macrophages. Also, populations of Xcr1+ type 1 classical dendritic cells (cDC1), Cd209a+ cDC2 and mature DCs (Ccr7, Fscn1) were detected. In humans, we uncovered macrophage and dendritic cell populations with gene expression patterns similar to those observed in mice in both vascular beds. In particular, core transcripts of the foamy/Trem2hi signature (TREM2, SPP1, GPNMB, CD9) mapped to a specific population of macrophages in human lesions. Cross-species data integration demonstrated transcriptionally proximal macrophage and dendritic cell populations in mice and humans.ConclusionsWe demonstrate conserved transcriptomics features of macrophages and dendritic cells in atherosclerosis in mice and humans, emphasizing the relevance of mouse models to study mononuclear phagocytes in atherosclerosis.

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mentioning

confidence: 83%

Integrated scRNA-seq analysis identifies conserved transcriptomic features of mononuclear phagocytes in mouse and human atherosclerosis

Zernecke

Erhard

Weinberger

et al. 2020

Preprint

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“…These different types of macrophages play fundamental roles in CNS development, homeostasis and disease, but their specific functions remain poorly defined. An important barrier to defining the subtype-specific functions of CNS macrophages has been a lack of genetic tools to specifically target these subpopulations, although there has been some progress in this regard in recent years ( Chappell-Maor et al, 2019 ; Werner et al, 2020 ; Wieghofer et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

A new genetic strategy for targeting microglia in development and disease

McKinsey

Lizama

Keown-Lang

et al. 2020

eLife

129

107

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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. 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 border-associated meningeal, perivascular and choroid plexus macrophages. Using immunofluorescent labeling, flow cytometry and Cre-dependent ribosomal immunoprecipitations, we describe P2ry12-CreER, a new tool for the genetic targeting of microglia. We use this new tool to track microglia during embryonic development and in the context of ischemic injury and neuro-inflammation. Because of the specificity and robustness of microglial recombination with P2ry12-CreER, we believe that this new mouse line will be particularly useful for future studies of microglial function in development and disease.

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“…In addition, Werner et al demonstrated that CXC motif chemokine receptor 4 (CXCR4) deficiency diminishes monocyte infiltration and dampens the levels of pattern recognition and defense response gene expression in monocyte-derived macrophages at the ischemic injury site, resulting in deteriorated ischemic stroke outcomes. These results indicate that CXCR4 distinguishing HSC-derived monocytes from microglia is a crucial factor in sustaining the beneficial role of monocytes through an innate immune system against neuroinflammation following ischemic stroke (116).…”

Section: Monocyte-derived Macrophagesmentioning

confidence: 78%

Monocyte Transmodulation: The Next Novel Therapeutic Approach in Overcoming Ischemic Stroke?

et al. 2020

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The immune response following neuroinflammation is a vital element of ischemic stroke pathophysiology. After the onset of ischemic stroke, a specialized vasculature system that effectively protects central nervous system tissues from the invasion of blood cells and other macromolecules is broken down within minutes, thereby triggering the inflammation cascade, including the infiltration of peripheral blood leukocytes. In this series of processes, blood-derived monocytes have a significant effect on the outcome of ischemic stroke through neuroinflammatory responses. As neuroinflammation is a necessary and pivotal component of the reparative process after ischemic stroke, understanding the role of infiltrating monocytes in the modulation of inflammatory responses may offer a great opportunity to explore new therapies for ischemic stroke. In this review, we discuss and highlight the function and involvement of monocytes in the brain after ischemic injury, as well as their impact on tissue damage and repair.

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Cxcr4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke

Cited by 147 publications

References 63 publications

Integrated scRNA-seq analysis identifies conserved transcriptomic features of mononuclear phagocytes in mouse and human atherosclerosis

Integrated scRNA-seq analysis identifies conserved transcriptomic features of mononuclear phagocytes in mouse and human atherosclerosis

A new genetic strategy for targeting microglia in development and disease

Monocyte Transmodulation: The Next Novel Therapeutic Approach in Overcoming Ischemic Stroke?

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