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Mapping Macrophage Polarization Over the Myocardial Infarction Time Continuum

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Mapping Macrophage Polarization Over the Myocardial Infarction Time Continuum Edinburgh Research Explorer Mapping macrophage polarization over the myocardial infarction time continuum Citation for published version: Mouton, AJ, DeLeon-Pennell, KY, Rivera Gonzalez, OJ, Flynn, ER, Freeman, TC, Saucerman, JJ, Garrett, MR, Ma, Y, Harmancey, R & Lindsey, ML 2018, 'Mapping macrophage polarization over the myocardial infarction time continuum', Basic research in cardiology, vol. 113, no. 4, pp. 26. https://doi.org/10.1007/s00395-018-0686-x Digital Object Identifier (DOI): 10.1007/s00395-018-0686-x Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Basic research in cardiology Publisher Rights Statement: This article is distributed under the terms of the Creative Commons Attribution, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 07. Oct. 2021 Basic Research in Cardiology (2018) 113:26 https://doi.org/10.1007/s00395-018-0686-x ORIGINAL CONTRIBUTION Mapping macrophage polarization over the myocardial infarction time continuum Alan J. Mouton1 · Kristine Y. DeLeon‑Pennell1,2 · Osvaldo J. Rivera Gonzalez1 · Elizabeth R. Flynn1 · Tom C. Freeman3 · Jefrey J. Saucerman4 · Michael R. Garrett5 · Yonggang Ma1 · Romain Harmancey1 · Merry L. Lindsey1,2 Received: 6 April 2018 / Accepted: 29 May 2018 © The Author(s) 2018 Abstract In response to myocardial infarction (MI), cardiac macrophages regulate infammation and scar formation. We hypothesized that macrophages undergo polarization state changes over the MI time course and assessed macrophage polarization transcrip- tomic signatures over the frst week of MI. C57BL/6 J male mice (3–6 months old) were subjected to permanent coronary artery ligation to induce MI, and macrophages were isolated from the infarct region at days 1, 3, and 7 post-MI. Day 0, no MI resident cardiac macrophages served as the negative MI control. Whole transcriptome analysis was performed using RNA- sequencing on n = 4 pooled sets for each time. Day 1 macrophages displayed a unique pro-infammatory, extracellular matrix (ECM)-degrading signature. By fow cytometry, day 0 macrophages were largely F4/80highLy6Clow resident macrophages, whereas day 1 macrophages were largely F4/80lowLy6Chigh infltrating monocytes. Day 3 macrophages exhibited increased proliferation and phagocytosis, and expression of genes related to mitochondrial function and oxidative phosphorylation, indicative of metabolic reprogramming. Day 7 macrophages displayed a pro-reparative signature enriched for genes involved in ECM remodeling and scar formation. By triple in situ hybridization, day 7 infarct macrophages in vivo expressed collagen I and periostin mRNA. Our results indicate macrophages show distinct gene expression profles over the frst week of MI, with metabolic reprogramming important for polarization. In addition to serving as indirect mediators of ECM remodeling, macrophages are a direct source of ECM components. Our study is the frst to report the detailed changes in the macrophage transcriptome over the frst week of MI. Keywords Myocardial infarction · Macrophage · Transcriptome · RNA-Seq · LV remodeling Introduction Electronic supplementary material The online version of this Myocardial infarction (MI) invokes a cardiac wound healing article (https​://doi.org/10.1007/s0039​5-018-0686-x) contains response that involves early initiation of infammation, fol- supplementary material, which is available to authorized users. lowed by robust scar formation in the infarct area. The mac- rophage is a key regulator of cardiac remodeling, providing * Merry L. Lindsey [email protected] both strong pro-infammatory signals early and reparative cues later [13, 24, 25, 41, 44]. Macrophages naturally reside 1 Department of Physiology and Biophysics, Mississippi in the healthy heart, largely derived from the embryonic yolk Center for Heart Research, University of Mississippi Medical sac, proliferating locally and overseeing normal tissue main- Center, 2500 North State St., Jackson, MS 39216‑4505, USA tenance [22, 34]. 2 Research Service, G.V. (Sonny) Montgomery Veterans In response to MI, circulating pro-infammatory ­Ly6Chigh Afairs Medical Center, Jackson, MS 39216, USA monocytes are rapidly recruited from bone marrow and 3 The Roslin Institute, University of Edinburgh, Easter Bush, splenic reservoirs to the infarcted area by the CC chemokine Midlothian, Scotland, UK CCL2/MCP-1, and require CCR2 (the endogenous receptor 4 Department of Biomedical Engineering, University for CCL2) for extravasation [14, 80]. Early post-MI, mono- of Virginia, Charlottesville, VA, USA cyte-derived macrophages promote infammation through 5 Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS 39216, USA Vol.:(0123456789)1 3 26 Page 2 of 18 Basic Research in Cardiology (2018) 113:26 release of pro-infammatory cytokines such as interleukin Coronary artery ligation (IL)-1β, a key regulator of post-MI infammation [70]. In the healthy heart and following MI, monocyte/mac- To produce permanent MI, mice underwent coronary artery rophage subpopulations are identifed by a limited number of ligation surgery as described previously and according to cell surface markers. Resident cardiac macrophages express the Guidelines for Experimental Models of Ischemia and high levels of the myeloid marker CD11b, as well as canoni- Infarction [12, 28, 39, 47, 94]. Mice were anesthetized with cal macrophage markers including CD14, CD86, CX3CR1, 2% isofurane, intubated, and ventilated. The left coronary F4/80, and MHC-II, and display an anti-infammatory M2 artery was ligated with 8–0 suture, and MI was confrmed by phenotype [63]. Resident macrophages are characterized left ventricle (LV) blanching and ST-segment elevation on by high expression of F4/80, while infltrating monocytes the EKG. Mice were administered buprenorphine (0.05 mg/ and monocyte-derived macrophages express F4/80 at lower kg body weight) immediately before surgery. levels [22, 62]. Following MI, F4/80highLy6Clow resident macrophages are rapidly replaced by pro-infammatory infl- trating F4/80lowLy6Chigh monocytes that are CCR2 high [22]; Echocardiography and necropsy by post-MI day 7, the macrophage phenotype shifts to a pre- dominantly anti-infammatory/pro-reparative M2 phenotype. LV physiology was determined by transthoracic echocar- Specifcally targeting macrophages to improve MI out- diography (Vevo 2100, VisualSonics; Toronto, CA) as comes has proven both promising and challenging, as described before and according to the Guidelines for Meas- therapeutic approaches successfully manipulating the mac- uring Cardiac Physiology in Mice [12, 28, 40, 47]. Mice rophage depend on both temporal and spatial factors [13, were anesthetized under 1–2% isofurane, and both long and 18]. For example, the early infammatory response is critical short-axis images were obtained. Measurements were taken for wound healing, as too little or excess infammation can on the terminal day and were averaged from three cardiac adversely afect remodeling; the same paradigm is true for cycles for each mouse. Following imaging, the hearts were the later reparative and fbrotic response [18]. While mac- removed and the left ventricle (LV) divided into remote and rophages have been extensively studied in steady state and infarct (which included border zone) regions. Each region aging hearts [10, 49, 61], as well as following pressure over- was separately weighed for infarct area estimation. The load [88], the full picture of the macrophage evolution over infarct sizes over the 3 MI time points had a coefcient of the frst week after MI has not been developed. variation of 18%, indicating gene variation was not likely Accordingly, the objective of this study was to combine due to diferences in infarct sizes. transcriptomics, fow cytometry, and cell physiology to provide a map of macrophage phenotypes in response to MI. We analyzed transcriptomic changes at days 1, 3, and Isolation of LV infarct macrophages 7 post-MI to refect the early infammatory, proliferative, and maturation phases. We hypothesized that macrophages LV macrophages were isolated from the infarct region by would undergo changes over the MI time course that range immunomagnetic separation as described previously [12, from pro-infammatory to reparative polarization. To our 28]. Excised LV tissue was rinsed and immediately minced knowledge, this is the frst study to report in detail the full and digested by collagenase II (Worthington; Lakewood, NJ) transcriptome changes that occur in cardiac macrophages and DNase solution in Hanks bufered saline solution. After that mediate post-MI wound
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