Single-Cell RNA-Seq Reveals the Transcriptional Landscape and Heterogeneity of Aortic Macrophages in Murine Atherosclerosis

Cochain, Clément; Vafadarnejad, Ehsan; Arampatzi, Panagiota; Pelisek, Jaroslav; Winkels, Holger; Ley, Klaus; Wolf, Dennis; Saliba, Antoine‐Emmanuel; Zernecke, Alma

doi:10.1161/circresaha.117.312509

Cited by 686 publications

(855 citation statements)

References 54 publications

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“…To evaluate whether similar neutrophil diversity could be observed in a distinct cardiovascular disease context, we analyzed scRNA-seq data from 2106 CD45 + cells isolated from control (371 cells) and atherosclerotic (1735 cells) aortas of Low densitiy lipoprotein receptor deficient (Ldlr-/-) mice (corresponding to a previously published dataset combined with novel data, see ref (16), and methods) ( Figure S8). Although only 66 cells corresponding to neutrophils were observed (Figure S8A), expression of the characteristic transcripts Siglecf and Icam1 appeared to localize to a subpopulation with segregated tSNE coordinates (Figure S8B-D).…”

Section: Scrna-seq Of Atherosclerotic Aortas Reveals Two Distinct Neumentioning

confidence: 99%

“…Diet-induced atherosclerosis was performed in Ldlr -/mice as previously described in ref (16). After 10 weeks of high fat diet feeding, macroscopically visible plaques were mechanically removed from aortas.…”

Section: Atherosclerosismentioning

confidence: 99%

“…The recent development of single-cell RNA-sequencing (scRNA-seq) in highthroughput allows investigating immune cell transcriptional states in disease models with high resolution, and has recently been employed to uncover novel immune cell transcriptional states in e.g. myocardial infarction (13), (14) or atherosclerosis (15), (16). Furthermore, novel methods of oligonucleotide-barcoded antibody labeling of cells prior to their processing for scRNA-seq allows a multimodal measurement of the expression of cell surface epitopes in addition to transcripts expression (17), (18) and the multiplexing of several biological samples in a single scRNA-seq library (19).…”

Section: Introductionmentioning

confidence: 99%

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Time-resolved single-cell transcriptomics uncovers dynamics of cardiac neutrophil diversity in murine myocardial infarction

Vafadarnejad

Rizzo

Krampert

et al. 2019

Preprint

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Objective-After myocardial infarction, neutrophils rapidly and massively infiltrate the heart, where they can promote both tissue healing and damage. Here, we investigated the dynamics of cardiac neutrophil heterogeneity after infarction.Methods and results-We employed single-cell transcriptomics (scRNA-seq) to investigate temporal neutrophil heterogeneity in the heart after murine myocardial infarction. At day 1, 3, and 5 after infarction, neutrophils could be delineated into six distinct clusters with specific time-dependent patterning and proportions. While the majority of neutrophils at day 1 were characterized by high expression of chemokines (e.g. Cxcl3, Ccl6), and putative activity of transcriptional regulators involved in hypoxic response (Hif1a) and emergency granulopoiesis (Cebpb), two major subsets of Siglecf hi (enriched for e.g. Icam1 and Tnf) and Siglecf low (Slpi, Ifitm1) neutrophils were found at 3 and 5 days. Flow cytometry analysis confirmed the presence of LY6G + SIGLECF hi and LY6G + SIGLECF low neutrophils in the heart from 3 days after infarction onwards. LY6G + SIGLECF hi neutrophils were absent from the bone marrow, blood and spleen, suggesting local acquisition of surface SIGLECF. Acquisition of the SIGLECF hi state was paralleled by features of neutrophil ageing and activation (ICAM1 hi CXCR4 hi CD49d hi CD62L low ). scRNA-seq of atherosclerotic aortas revealed two neutrophil subsets with gene expression patterns reminiscent of the major Siglecf hi and Siglecf low cardiac neutrophil subpopulations, revealing that these populations may be present across distinct contexts of cardiovascular inflammation.Conclusion-Altogether, our data provide a time-resolved census of neutrophil diversity and gene expression dynamics in the mouse ischemic heart at the single-cell level, and suggests that temporal neutrophil heterogeneity is in part driven by local transition to a SIGLECF hi state.

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Section: Scrna-seq Of Atherosclerotic Aortas Reveals Two Distinct Neumentioning

confidence: 99%

Section: Atherosclerosismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Time-resolved single-cell transcriptomics uncovers dynamics of cardiac neutrophil diversity in murine myocardial infarction

Vafadarnejad

Rizzo

Krampert

et al. 2019

Preprint

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“…For example, classically polarized M1 and M2 macrophages undergo rapid repolarization via a Nrf2-driven transcriptional program into an atherogenic polarization state upon exposure to moLDL 31 . In this study, we determined that macrophages isolated from early-stage human atheromas lack upregulation of classical M1 (CD80/86, iNOS) or M2 (Arg1, CD206) markers, or markers previously reported in macrophage polarization states present in late-stage plaque (TREM2, Nrf2, Atf1) 27,30,31 . Instead, these cells downregulated many genes involved in the processes of efferocytosis, cholesterol processing, and the degradative pathway required for proper removal of both apoptotic cells and moLDL, while upregulating immunogenic enzymes such as PADI3.…”

Section: Discussionmentioning

confidence: 98%

“…In mice, resident aortic macrophages are embryonically-derived, self-renewing cells characterized by the expression of scavenger receptors, MHC II and efferocytic receptors 22 . In mouse models two macrophage sub-types emerge within atherosclerotic lesions: haematopoietically-derived inflammatory (M1) macrophages, and a TREM2 + population unique to the atherosclerotic plaque that expresses a mixture of resident-macrophage markers and markers of alternatively activated (M2) cells 27 . While the ontology of human aortic and cardiac macrophages are not well-understood, macrophages with markers of M1-polarization (iNOS, CD86), M2-polarization (MR, dectin-1), and TREM2 + -polarization (TREM2, CD9 hi ) have been identified in established plaques 27,28 .…”

Section: Introductionmentioning

confidence: 99%

GATA2 Expression by Intima-Infiltrating Macrophages Drives Early Atheroma Formation

Akingbasote

et al. 2019

Preprint

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Aberrant macrophage polarization is a major contributor to the onset and progression of atherosclerosis. Despite this, macrophage polarization during in early stages of human atherosclerotic disease is poorly understood. Using transcriptomic analysis of macrophages recovered from early-stage human atherosclerotic lesions, we have identified a unique gene expression profile dissimilar to that observed in later stages of disease that is characterized by upregulation of the hematopoietic transcription factor GATA2. GATA2 overexpression in vitro recapitulated defects observed in patient macrophages, including deficiencies in the uptake and processing of apoptotic cells, and in the catalysis of atherogenic protein modifications, with GATA2 knockdown abrogating these defects. Our data describe a previously unreported macrophage differentiation state present in early atheroma formation and identifies GATA2 as a driver of macrophage functional defects during the early stages of atherosclerosis in humans.

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Novel insights into the regulation of cellular catabolic metabolism in macrophages through nuclear receptors

2022

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Regulation of cellular catabolic metabolism in immune cells has recently become a major concept for resolution of inflammation. Nuclear receptors (NRs), including peroxisome proliferator activator receptors, 1,25‐dihydroxyvitamin D (3) receptor, liver X receptors, glucocorticoid receptors, oestrogen‐related receptor α and nuclear receptor 4A1, have been identified as major modulators of inflammation, affecting innate immune cells, such as macrophages. Evidence emerges on how NRs regulate cellular metabolism in macrophages during inflammatory processes and contribute to the resolution of inflammation. This could have new implications for our understanding of how NRs shape immune responses and inform anti‐inflammatory drug design. This review will highlight the recent developments about NRs and their role in cellular metabolism in macrophages.

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Single-Cell RNA-Seq Reveals the Transcriptional Landscape and Heterogeneity of Aortic Macrophages in Murine Atherosclerosis

Cited by 686 publications

References 54 publications

Time-resolved single-cell transcriptomics uncovers dynamics of cardiac neutrophil diversity in murine myocardial infarction

Time-resolved single-cell transcriptomics uncovers dynamics of cardiac neutrophil diversity in murine myocardial infarction

GATA2 Expression by Intima-Infiltrating Macrophages Drives Early Atheroma Formation

Novel insights into the regulation of cellular catabolic metabolism in macrophages through nuclear receptors

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