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Self-Renewing Resident Cardiac Macrophages Limit Adverse Remodeling Following Myocardial Infarction

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Self-Renewing Resident Cardiac Macrophages Limit Adverse Remodeling Following Myocardial Infarction JOURNAL CLUB 3/19/19 SAHIL MAHAJAN ARTICLES https://doi.org/10.1038/s41590-018-0272-2 Corrected: Publisher Correction Self-renewing resident cardiac macrophages limit adverse remodeling following myocardial infarction Sarah A. Dick1,2,11, Jillian A. Macklin 1,2,3,4,11, Sara Nejat 1,11, Abdul Momen1, Xavier Clemente-Casares1, Marwan G. Althagafi1,4, Jinmiao Chen 5,6, Crystal Kantores 1, Siyavash Hosseinzadeh1,4, Laura Aronoff1,4, Anthony Wong 1,7, Rysa Zaman 1,7, Iulia Barbu1,7, Rickvinder Besla1,4, Kory J. Lavine8, Babak Razani8,9, Florent Ginhoux 5,6, Mansoor Husain1,2,3,4,10, Myron I. Cybulsky1,4,10, Clinton S. Robbins1,4,7,10 and Slava Epelman 1,2,3,4,7,10* Macrophages promote both injury and repair after myocardial infarction, but discriminating functions within mixed populations remains challenging. Here we used fate mapping, parabiosis and single-cell transcriptomics to demonstrate that at steady state, TIMD4+LYVE1+MHC-IIloCCR2− resident cardiac macrophages self-renew with negligible blood monocyte input. Monocytes par- tially replaced resident TIMD4–LYVE1–MHC-IIhiCCR2− macrophages and fully replaced TIMD4−LYVE1−MHC-IIhiCCR2+ macro- phages, revealing a hierarchy of monocyte contribution to functionally distinct macrophage subsets. Ischemic injury reduced TIMD4+ and TIMD4– resident macrophage abundance, whereas CCR2+ monocyte-derived macrophages adopted multiple cell fates within infarcted tissue, including those nearly indistinguishable from resident macrophages. Recruited macrophages did not express TIMD4, highlighting the ability of TIMD4 to track a subset of resident macrophages in the absence of fate map- ping. Despite this similarity, inducible depletion of resident macrophages using a Cx3cr1-based system led to impaired cardiac function and promoted adverse remodeling primarily within the peri-infarct zone, revealing a nonredundant, cardioprotective role of resident cardiac macrophages. schemic cardiovascular disease remains the leading cause of cytes to the adult CD64+ cardiac macrophage pool are not known. mortality worldwide1. After a myocardial infarction, an inflam- However, after birth, the slow recruitment of invading monocyte- Imatory response is directed to the site of injury, resulting in derived macrophages from circulation leads to competition for tis- structural and biochemical changes that can lead to adverse cardiac sue residency, and it is not clear whether monocyte-independent remodeling and dysfunction manifesting clinically as heart failure2. populations remain13. Macrophages are specialized mononuclear phagocytes that reside in Circulating monocytes express CCR2, a chemokine recep- all tissues from the earliest stages of development and have particu- tor important for migration14, and are enriched in components larly important roles in the response to injury3–6. The mammalian of the NLRP3 inflammasome. After tissue injury, CCR2+ mono- neonatal heart has a remarkable capacity to fully regenerate after cytes and macrophages can produce IL-1β5 , a pro-inflammatory injury7. Clodronate liposomal depletion of neonatal macrophages cytokine that promotes cardiovascular disease15. In contrast, resi- prevents regeneration, in part through macrophage-specific expres- dent CCR2− macrophages are primarily of embryonic origin and sion of growth factors such as IGF-1 and other mechanisms yet to be promote angiogenesis and cardiomyocyte proliferation, similar to characterized8–10. After ischemic injury in adult mice, both excessive neonatal macrophages8,9,16. However, beyond these observations, numerical expansion of macrophages8,11 and nonselective depletion more-detailed understanding of cardiac macrophage heterogeneity of macrophages12 limit cardiac repair through excessive inflam- is lacking. matory tissue damage and impaired scar formation, respectively. Here we investigated cardiac macrophage heterogeneity at steady Macrophage composition in tissue is both heterogeneous at steady state, plasticity after infarction and the role of resident macrophages state and highly dynamic after injury. Within the adult heart, the in repair. Through the combined use of genetic fate mapping, long- majority of resident cardiac macrophages originate from embryonic term parabiosis studies and single-cell RNA sequencing (scRNA- development, both from early embryonic day 8.5 (E8.5) erythromy- seq), we observed that the healthy adult myocardium contains eloid progenitors and also later from fetal monocytes5. The relative four populations of macrophages, including a subset that is main- contributions of erythromyeloid progenitor cell–derived fetal liver tained independently of blood monocytes (TIMD4+LYVE1+MHC- monocytes and emerging hematopoietic stem cell–derived mono- IIloCCR2–), a subset that is partially replaced by monocytes 1Toronto General Hospital Research Institute, University Health Network (UHN), Toronto, Canada. 2Ted Rogers Centre for Heart Research, Toronto, Canada. 3Department of Medicine, University of Toronto, Toronto, Canada. 4Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada. 5Singapore Immunology Network(SIgN), Agency for Science Technology and Research (A*STAR), Singapore, Singapore. 6Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, Shanghai, China. 7Department of Immunology, University of Toronto, Toronto, Canada. 8Division of Cardiology, Washington University School of Medicine, St Louis, MO, USA. 9John Cochran VA Medical Center, St Louis, MO, USA. 10Peter Munk Cardiac Centre, Toronto, Canada. 11These authors contributed equally: Sarah A. Dick, Jillian A. Macklin, Sara Nejat. *e-mail: [email protected] NATURE IMMUNOLOGY | VOL 20 | JANUARY 2019 | 29–39 | www.nature.com/natureimmunology 29 ARTICLES NATURE IMMUNOLOGY (TIMD4−LYVE1–MHC-IIhiCCR2−) and two CCR2+MHC-IIhi sub- Cluster 5 was enriched in many interferon-stimulated genes such as sets that are fully replaced by monocytes. Ischemic injury induced Irf7, Isg20 and Ifit1 (termed the Isg cluster; Fig. 1d,f). great diversification of these macrophage subsets. After myocardial We performed pathway analysis by individually comparing the infarction, the phosphatidylserine receptor TIMD417 and CCR2 Timd4 cluster to other clusters. Timd4 cluster pathways were focused emerged as mutually exclusive markers of resident macrophages and on homeostatic and regenerative functions; that is, endocytosis, lys- recruited macrophages, respectively. Resident macrophage abun- osome function, angiogenesis and regeneration (Fig. 1g). Relative to dance within the infarct zone was markedly reduced after infarc- the Timd4 cluster, translational-ribosomal pathways were strongly tion and slowly increased through in situ proliferation. Depletion upregulated in the Mhc-II, Ccr2 and Isg clusters, whereas classic of diphtheria toxin receptor–labeled resident (Cx3cr1-expressing) inflammatory pathways, including respiratory burst, response to macrophages promoted adverse cardiac remodeling primarily in interleukin 12, interferon-γ and type I interferon, were enriched in the peri-infarct zone, a vulnerable region surrounding infarct tissue. the Ccr2 and Isg clusters (Fig. 1g). These data reveal the existence Despite the ability of a small portion of recruited, monocyte-derived of unique, cluster-specific functions in macrophages at steady state. macrophages to assume a nearly identical transcriptional fate to the resident macrophage populations, resident cardiac macrophages Single-cell trajectories reveal developmental relationships. had nonredundant, spatially localized cardioprotective functions. To determine whether hypothetical developmental relationships exist between monocytes and macrophage clusters, we reclustered Results these populations (clusters 1–5) to provide trajectories of single Single-cell analyses show unique cardiac macrophage subsets. cell–based changes in gene expression (Fig. 2a). Seurat-defined Flow cytometric analysis of cardiac CD45+CD64+CD11b+ mac- clusters were superimposed on a pseudotime trajectory produced rophages revealed a single CCR2–MHC-IIlo macrophage subset in by the Monocle24 algorithm, which revealed that macrophages neonatal mice at post-natal day 14 (P14), whereas in adult mice in the Timd4 cluster occupied a separate trajectory branch (B1; (> 12 weeks old), we detected additional CCR2+MHC-IIhi and Fig. 2b). Monocytes and macrophages found in the Ccr2 and Isg CCR2–MHC-IIhi macrophage populations (Fig. 1a). To quantify clusters occupied a second branch (B2; Fig. 2b), whereas mac- monocyte dependence, we paired Ccr2−/− mice (Rosa26+/+), which rophages in the Mhc-II cluster straddled all three branches (B3; lack circulating Ly6Chi monocytes, with Ccr2+/+ mice, which car- Fig. 2b). The Mpath25 algorithm demonstrated similar ordering, ried a constitutively expressed gene encoding the membrane-local- suggesting that macrophages in the Isg cluster could arise from the ized TdTomato (Td) reporter in the Rosa26 locus (Rosa26mTmG/mTmG; Ccr2 cluster, rather than monocytes (Fig. 2c), which was confirmed R26 mTmG), for 6 months. Cardiac tissue from the Ccr2−/− mice indi- by a restricted Monocle analysis (Fig. 2d). cated that most CCR2+ macrophages (>80%) and a smaller percent- Gene expression was then plotted as a function of pseudo- age of CCR2–MHC-IIhi macrophages (~25%) within the heart were time in Monocle to track changes across different macrophage replaced with macrophages derived from Ccr2+/+ (Td +) monocytes states. Klf2, Mafb and Maf expression was low in the Ccr2 cluster,
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