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Limited proliferation capacity of aortic intima resident macrophages requires monocyte recruitment for atherosclerotic plaque progression

Abstract

Early atherosclerosis depends upon responses by immune cells resident in the intimal aortic wall. Specifically, the healthy intima is thought to be populated by vascular dendritic cells (DCs) that, during hypercholesterolemia, initiate atherosclerosis by being the first to accumulate cholesterol. Whether these cells remain key players in later stages of disease is unknown. Using murine lineage-tracing models and gene expression profiling, we reveal that myeloid cells present in the intima of the aortic arch are not DCs but instead specialized aortic intima resident macrophages (MacAIR) that depend upon colony-stimulating factor 1 and are sustained by local proliferation. Although MacAIR comprise the earliest foam cells in plaques, their proliferation during plaque progression is limited. After months of hypercholesterolemia, their presence in plaques is overtaken by recruited monocytes, which induce MacAIR-defining genes. These data redefine the lineage of intimal phagocytes and suggest that proliferation is insufficient to sustain generations of macrophages during plaque progression.

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Fig. 1: Profiling MacAIR in the steady state.
Fig. 2: MacAIR are Csf1-dependent.
Fig. 3: MacAIR develop from bone marrow progenitors and seed the aorta at birth.
Fig. 4: MacAIR are maintained independent of circulating progenitors and proliferate within the tissue.
Fig. 5: MacAIR promote monocyte recruitment in early atherosclerotic lesions.
Fig. 6: Fate mapping MacAIR in the progression of atherosclerosis.
Fig. 7: Aortic intima microenvironment promotes shared gene programs between resident macrophages in the steady state and disease progression.

Data availability

Gene expression data (bulk RNA-seq or scRNA-seq) have been uploaded to the Gene Expression Omnibus (GEO) repository for public availability under accession codes GSE116271, GSE116239, GSE154817 and GSE154921. All other data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

Flt3Cre mice were provided by D. Mann (Washington University School of Medicine; WUSM); Flt3−/−, Flt3l−/−, SNZ22GFP, L-MycGFP and Zbtb46GFP mice were provided by K. Murphy (WUSM); IL-34−/− and CCR2GFP mice were provided by M. Colonna (WUSM); op/op mice were provided by E. Unanue (WUSM); and Csf2rb−/− mice were provided B. Edelson (WUSM). We also thank M. Vail (University of Minnesota), the WUSM Flow Cytometry Core Facility, WUSM McDonnell Genome Institute and WUSM Genome Technology Access Center for technical assistance on this study. Research was supported by the National Institutes of Health (NIH) R00 HL138163 (to J.W.W.), AHA 16SDGG30480008 (to B.H.Z.), T32 AI007313 (to C.G.T.), P01 AI35296 (to B.T.F.) and NIH R37 AI049653 and DP1DK109668 (to G.J.R.). J.W.W. was supported by NIH 2T32DK007120-41 and AHA 17POST33410473. J-H.C. was supported by the Korean Health Technology R&D project HI15C0399 and Ministry of Health, Welfare & Family Affairs (South Korea). K.Z. was supported by the Government of Russian Federation (grant no. 08-08).

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Contributions

This project was conceived and designed by J.W.W., M.N.A., B.H.Z., J-H.C. and G.J.R. Samples and materials were provided by J.W.W., B.T.F., B.H.Z., J-H.C. and G.J.R. Experiments were performed and analyzed by J.W.W., K.Z., K-W.K., S.I., B.T.S., P.R.S., K.K., A.E., S.H.K., C.G.T., M.W., S.E., K.J.L., B.H.Z. and J-H.C. All authors contributed to the preparation of this manuscript.

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Correspondence to Jesse W. Williams.

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The authors declare no competing interests.

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Peer review information Jamie D. K. Wilson was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Profiling aorta macrophage populations by bulk RNA-seq.

Bulk sorted MacAIR from C57BL/6 mice and adventitia, intima non-foamy, and intima foamy macrophages from 26-week HFD fed ApoE−/− mice were profiled for gene expression by RNA-seq19. Gene groupings for (a) macrophage and DC genes, (b) foamy and adventitia macrophage genes, (c) MacAIR enriched genes, and (d) genes associated with chemokine signaling in myeloid cells. Data are mean expression values derived from pooled macrophages from two biological replicates for MacAIR derived from 10-pooled aorta each, and three biological replicates each for ApoE−/− samples from 6-pooled aorta each.

Extended Data Fig. 2 MacAIR are detected across multiple scRNA-seq approaches.

(a) scRNA-seq data from C57BL/6 total CD45+ cells was integrated with two published studies where CD45+ aorta cells from chow-fed Ldlr−/− mice22 and atherosclerosis regression samples23, identifying 10 unique clusters. (b) Top 12 enriched MacAIR genes were used to define MacAIR cluster as cluster 4, presented as relative expression. (c) MacAIR were detectable in all three datasets with a relative abundance between 2.00–9.28%. (d) cDC1 genes (Zbtb46, Flt3, Itgae, Xcr1, Snx22, Mycl, and Rab43) were interrogated against the integrated dataset, defining a unique DC population. (e) Itgae and Xcr1 gene expression plotted on integrated t-SNE cluster map.

Extended Data Fig. 3 Differential gene expression between clusters of integrated dataset of C57BL/6, Ldlr−/−, and regression scRNA-seq experiments.

Top differentially expressed genes are listed with expression level across the 10 unique groups identified by unsupervised clustering of the integrated data of C57BL/6, chow fed Ldlr-/−22, and regression23 scRNA-seq datasets.

Extended Data Fig. 4 Profiling myeloid cells in the aorta.

Spleen and aorta samples from (a) SNX22gfp and (b) L-Mycgfp reporter mice were assessed for presence of cDC1 in respective tissues, GFP (green) and Dapi (blue). In panel B aorta, sample was co-stained with CD45 (red) and MHC II (white) antibody. Aorta from XCR1-venus reporter mice were isolated and stained for MHC II (red) or CD45 (white) expression by antibody labeling, then imaged in whole-mount for presence of cDC1 in the (c) aortic arch intima, (d) adventitia, and (e) aortic valve. C57Bl/6 (WT) aorta was isolated and stained for CD103 (green), MHC II (red), and CD45 (white) by antibody labeling and imaged by confocal microscopy for cDC1 presence in the (f) intima of the aortic arch or (g) the adventitia of the aorta. Embryonic labeling was performed using CD115creER Rosa26-mTmG mice. Aorta were collected from adult animals and assessed for GFP (green) and Tomato (red) expression in mice labeled at (h) E11.5, and co-stained with CD45 (white) in mice labeled at (i) E14.5. Data are representative of (a) n = 3, (b) n = 3, (ce) n = 6 in two experiments, (f, g) n = 6 in two experiments, (h) n = 3, and (i) n = 5 in two experiments.

Extended Data Fig. 5 Atherosclerotic plaque development in the aorta of hypercholesterolemic mice following acute depletion of MacAIR.

(a) Following the schematic, CX3CR1creER CD115-stop-DTR mice were used to conditionally express DTR on MacAIR by gavage with tamoxifen, waiting three weeks to allow circulating cells to repopulation from DTR-negative progenitors. MacAIR were depleted by i.p. injection of diphtheria toxin and hypercholesterolemia induced by i.v. injection of AAV-PCSK9. Mice were started on HFD the following day. Mice were sacrificed and assessed for plaque area in the aortic arch by oil red o (ORO) staining. (b) Representative images of ORO staining and en face imaging. (c) Quantification of plaque area on the aortic arch. Data are from n = 7, Cntl and n = 4 for DTR-group and are the result of a single experiment, error bars represent SEM.

Extended Data Fig. 6 Fate-mapping MacAIR during atherosclerosis progression in bone marrow transplant model.

Recipient Ldlr−/− mice were lethally irradiated and reconstituted with CX3CR1creER Rosa26-lsl-Tomato bone marrow. Mice were rested for 8-weeks for full hematopoietic reconstitution, then treated with tamoxifen by gavage to induce Tomato expression in CX3CR1-expressing cells, including MacAIR. (a) Three weeks after tamoxifen labeling, MacAIR remained Tomato+ (red) positive. Mice were then fed HFD and assessed for plaque development at (b) 10 days and (c) 28 days. MacAIR can be observed by Tomato-expression, whereas recruited cells were stained with CD68 (green) antibody. Samples are all en face whole mount confocal images of the aortic arch. Images are representative of n = 3 for each time point.

Extended Data Fig. 7 Csf2rb−/− Ldlr−/− mice fed HFD for 12 days.

Csf2rb+/- Ldlr−/− or Csf2rb−/− Ldlr−/− mice were fed HFD for 12 days to induce atherosclerotic lesions in the aortic arch. Aorta were stained for MHC II (red) and imaged by tile scanning whole mount confocal microscopy for macrophage burden and morphologic changes associated with foamy cell development. Three representative images (n = 7 for Csf2rb+/- Ldlr−/−) or (n = 4 Csf2rb−/− Ldlr−/−) were selected from a single experiment.

Extended Data Fig. 8 Differential gene expression analysis of scRNA-seq of CD45+ cells from Ldlr−/− aorta after 21-days HFD feeding.

The top 10 enriched genes for each cluster are reported for scRNA-seq analysis of total CD45+ cells from Ldlr−/− mice fed HFD for 21 days.

Extended Data Fig. 9 Integrated scRNA-seq analysis across atherosclerosis progression.

(a) scRNA-seq data from sorted CD45+ aorta cells isolated from C57Bl/6, 21-day HFD Ldlr−/−, and 12-week HFD Ldlr−/− mice was integrated and clustered into 16 populations. (b) All clusters were represented across unique time points. (c) MacAIR geneset (Mmp12, Il1b, Lgals3, Nes, Rgs1, Acp5, Asb2, Itgax, Cadm1, Gngt2, Cd9, Bcl2a1a) expression analysis of integrated cluster map and across time points. (d) Foamy macrophage geneset (Fabp4, Ctsl, Atp6v0d2, Gpnmb, Fabp5, Htra1, Epb41l3, Pld3) expression analysis of integrated cluster map and across time points. (e) Human foamy macrophage geneset (Gpx1, Pfdn5, Tpt1, Eef1a1, Ctb, B2m, Tmsb4x, Fth1, Ftl, Tmsb10, Cd63, Lgals1, Fcer1g, Npc2, Serf2, Ybx1, Psap, Apoc1, Apoe, Cstb, Ctsb, Vim, RnaseI, Fabp5, Plin2, Ccl2) expression analysis in the murine integrated scRNA-seq cluster map, suggesting shared gene expression programs between human and murine foamy macrophage subsets.

Extended Data Fig. 10 Differential gene expression from integrated scRNA-seq analysis across atherosclerosis time course.

scRNA-seq data from sorted CD45+ aorta cells isolated from C57Bl/6, 21-day HFD Ldlr−/−, and 12-week HFD Ldlr−/− mice were integrated and clustered into 16 populations. Top 10 differentially expressed genes are shown for each cluster.

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Williams, J.W., Zaitsev, K., Kim, KW. et al. Limited proliferation capacity of aortic intima resident macrophages requires monocyte recruitment for atherosclerotic plaque progression. Nat Immunol 21, 1194–1204 (2020). https://doi.org/10.1038/s41590-020-0768-4

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