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• W4225282388 abstract "HomeCirculationVol. 145, No. 18Single-Cell RNA Sequencing Reveals a Distinct Immune Landscape of Myeloid Cells in Coronary Culprit Plaques Causing Acute Coronary Syndrome Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBSingle-Cell RNA Sequencing Reveals a Distinct Immune Landscape of Myeloid Cells in Coronary Culprit Plaques Causing Acute Coronary Syndrome Takuo Emoto, MD, PhD, Hiroyuki Yamamoto, MD, PhD, Tomoya Yamashita, MD, PhD, Tomofumi Takaya, MD, PhD, Takahiro Sawada, MD, PhD, Shintaro Takeda, Masayuki Taniguchi, PhD, Naoto Sasaki, MD, PhD, Naofumi Yoshida, MD, PhD, Yoshihiro Saito, MD, Tharini Sivasubramaniyam, PhD, Hiromasa Otake, MD, PhD, Tomoyuki Furuyashiki, MD, PhD, Clinton S. Robbins, PhD, Hiroya Kawai, MD, PhD and Ken-ichi Hirata, MD, PhD Takuo EmotoTakuo Emoto https://orcid.org/0000-0001-7425-4087 Division of Cardiovascular Medicine, Department of Internal Medicine (T.E., T.Y., S.T., N.Y., Y.S., H.O., K.H.), Kobe University Graduate School of Medicine, Japan. *T. Emoto and H. Yamamoto contributed equally. Search for more papers by this author , Hiroyuki YamamotoHiroyuki Yamamoto https://orcid.org/0000-0002-5268-4606 Division of Cardiovascular Medicine, Department of Internal Medicine, Hyogo Brain and Heart Center, Himeji, Japan (H.Y., T.T., T. Sawada, H.K.). *T. Emoto and H. Yamamoto contributed equally. Search for more papers by this author , Tomoya YamashitaTomoya Yamashita Correspondence to: Tomoya Yamashita, MD, PhD, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 6500017, Japan. Email E-mail Address: [email protected] https://orcid.org/0000-0003-0267-3842 Division of Cardiovascular Medicine, Department of Internal Medicine (T.E., T.Y., S.T., N.Y., Y.S., H.O., K.H.), Kobe University Graduate School of Medicine, Japan. Search for more papers by this author , Tomofumi TakayaTomofumi Takaya https://orcid.org/0000-0001-5775-8072 Division of Cardiovascular Medicine, Department of Exploratory and Advanced Search in Cardiology (T.T., H.K.), Kobe University Graduate School of Medicine, Japan. Division of Cardiovascular Medicine, Department of Internal Medicine, Hyogo Brain and Heart Center, Himeji, Japan (H.Y., T.T., T. Sawada, H.K.). Search for more papers by this author , Takahiro SawadaTakahiro Sawada Division of Cardiovascular Medicine, Department of Internal Medicine, Hyogo Brain and Heart Center, Himeji, Japan (H.Y., T.T., T. Sawada, H.K.). Search for more papers by this author , Shintaro TakedaShintaro Takeda Division of Cardiovascular Medicine, Department of Internal Medicine (T.E., T.Y., S.T., N.Y., Y.S., H.O., K.H.), Kobe University Graduate School of Medicine, Japan. Search for more papers by this author , Masayuki TaniguchiMasayuki Taniguchi Division of Pharmacology (M.T., T.F.), Kobe University Graduate School of Medicine, Japan. Search for more papers by this author , Naoto SasakiNaoto Sasaki Laboratory of Medical Pharmaceutics, Kobe Pharmaceutical University, Japan (N.S.). Search for more papers by this author , Naofumi YoshidaNaofumi Yoshida Search for more papers by this author , Yoshihiro SaitoYoshihiro Saito Division of Cardiovascular Medicine, Department of Internal Medicine (T.E., T.Y., S.T., N.Y., Y.S., H.O., K.H.), Kobe University Graduate School of Medicine, Japan. Search for more papers by this author , Tharini SivasubramaniyamTharini Sivasubramaniyam Toronto General Research Institute, University Health Network, Canada (T. Sivasubramaniyam, C.S.R.). Search for more papers by this author , Hiromasa OtakeHiromasa Otake https://orcid.org/0000-0001-9953-0551 Division of Cardiovascular Medicine, Department of Internal Medicine (T.E., T.Y., S.T., N.Y., Y.S., H.O., K.H.), Kobe University Graduate School of Medicine, Japan. Search for more papers by this author , Tomoyuki FuruyashikiTomoyuki Furuyashiki https://orcid.org/0000-0001-8089-8399 Division of Pharmacology (M.T., T.F.), Kobe University Graduate School of Medicine, Japan. Search for more papers by this author , Clinton S. RobbinsClinton S. Robbins Toronto General Research Institute, University Health Network, Canada (T. Sivasubramaniyam, C.S.R.). Department of Laboratory Medicine and Pathobiology (C.S.R.), University of Toronto, Canada. Department of Immunology (C.S.R.), University of Toronto, Canada. Peter Munk Cardiac Centre, Toronto, Canada (C.S.R.). Search for more papers by this author , Hiroya KawaiHiroya Kawai Division of Cardiovascular Medicine, Department of Exploratory and Advanced Search in Cardiology (T.T., H.K.), Kobe University Graduate School of Medicine, Japan. Search for more papers by this author and Ken-ichi HirataKen-ichi Hirata Division of Cardiovascular Medicine, Department of Internal Medicine (T.E., T.Y., S.T., N.Y., Y.S., H.O., K.H.), Kobe University Graduate School of Medicine, Japan. Search for more papers by this author Originally published2 May 2022https://doi.org/10.1161/CIRCULATIONAHA.121.058414Circulation. 2022;145:1434–1436Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: May 2, 2022: Previous Version of Record Acute coronary syndrome (ACS) results from a plaque-related acute thrombus, causing primary ischemic cardiomyopathy or lethal arrhythmia. We aimed to understand how immune cells affect the vulnerability of coronary plaques and find a way to regulate immune cells to stabilize vulnerable plaques and prevent ACS. Recently, human carotid atherosclerotic lesions were characterized by single-cell RNA sequencing.1 Although the biology of the atherosclerotic process is suspected to be similar, clinical and pathological studies suggested differences in plaque morphology and characteristics between carotid and coronary arteries.2 Directional coronary atherectomy, the only method to obtain coronary plaques from patients, has been reported to be beneficial for limited patients. Herein, we provide the first detailed characterization of the immune cell composition between coronary culprit plaques causing ACS (ACS plaques) and those causing chronic coronary syndrome (CCS plaques) obtained by directional coronary atherectomy, allowing us to identify new therapeutic targets to prevent ACS.High-intensity signals in coronary plaques on noncontrast T1-weighted magnetic resonance imaging suggest increased risks of coronary events by morphological evaluation. Therefore, we prospectively enrolled 4 patients with CCS without high-intensity signals in coronary plaques and 3 patients with ACS between October 2020 and June 2021. All participants provided written, informed consent on enrollment. The study was approved by the Ethics Committee of Kobe University and Hyogo Brain and Heart Center (B200139) and registered with the University hospital Medical Information Network Clinical Trials Registry (UMIN 000040747). Whereas 2 of the 4 patients with CCS had been treated with statins or antidiabetes drugs, none of the 3 patients with ACS received these drugs, although they had risk factors. All viable CD45+ immune cells were sorted from the pooled plaque samples and applied to the 10X platform. All sequencing data can be accessed at GSE184073. The data and methods that support the findings of this study are available from the corresponding author on reasonable request.The pooled CD45+ immune cells from the CCS and ACS plaques were projected onto uniform manifold approximation and projection to obtain T, NK, B, and myeloid cell clusters. Reclustering of the myeloid cell cluster by uniform manifold approximation and projection revealed 6 distinct clusters (macrophages [My.0, My.1, My.2], S100A8/9/12 monocytes [My.3], mast cells and others [My.4], and dendritic cells [My.5]). My.0, My.1, and My.2 were determined as macrophage clusters expressing macrophage markers such as ITGAM, CD14, CD68, and CSF1R. My.3 was categorized as a newly recruited monocyte subcluster in tissue, S100A8/9/12+ monocytes, selectively expressing S100A8/9/12, LYZ, and CTSS.3 My.4 was characterized by mast cell markers including KIT, without ITGAM expression, although other ITGAM-negative myeloid cells could contaminate My.4. My.5 was characterized by dendritic cell markers, including CLEC10A, FCER1A, CD1c, and HLAs.Consistent with the previous article analyzing carotid atherosclerotic lesions,1 My.0 and My.2 were enriched in proinflammatory cytokines and Toll-like receptors and were distinguished by the characteristic expression of several genes; My.2 had selectively higher CXCL3 expression, tended to have higher IL1B expression than did My.0, and showed an absence of TREM2 or C1Q, whereas My.0 selectively expressed TNF. In contrast with My.0 or My.2, My.1 showed an absence of proinflammatory cytokines and had a significantly higher C1Q expression and tended to have slightly higher TREM2 expression than did My.0, suggesting My.1 as profibrotic macrophages because it was clearly demonstrated that TREM2+ CD9+ profibrotic macrophages with higher expression of C1Q were reported to expand in patients with liver fibrosis.4 Each macrophage subcluster contributed to reverse cholesterol transport via different pathways, which is characteristic in our coronary atherosclerotic lesions; My.2 expressed ABCA1 and MARCO, whereas My.0 and My.1 expressed APOE, APOC1, and MSR1. To represent characteristics of each macrophage cluster, we termed My.0 “TNF+ macrophages,” My.1 “C1Q+ TREM2+ fibrotic macrophages,” and My.2 “CXCL3+ IL1B+ inflammatory macrophages” (Figure [A through C]).Download figureDownload PowerPointFigure. Clustering of myeloid cells showing a distinct unique compositional difference between the chronic coronary syndrome and acute coronary syndrome plaques. A, Clustering of myeloid cells by uniform manifold approximation and projection (UMAP) in combined populations of the chronic coronary syndrome and acute coronary syndrome plaques. B, Violin plots depicting the single-cell gene expression of canonical myeloid cell markers or important functional genes. C, Heat map of the top 10 genes that separate each cluster from others. D, Clustering of myeloid cells by UMAP separately for the chronic coronary syndrome plaques and acute coronary syndrome plaques.The myeloid cell cluster exhibited a unique compositional difference between the CCS and ACS plaques. It is interesting that S100A8/9/12+ monocytes (My.3), mast cells and others (My.4), and CXCL3+ IL1B+ inflammatory macrophages (My.2) were detected only in the ACS plaques (Figure [D]). CXCL3+ IL1B+ inflammatory macrophages (My.2) and S100A8/9/12+ monocytes (My.3), detected only in the ACS plaques, expressed IL1B at a higher level than did the other clusters, which supports the results of the CANTOS trial.5 CXCL3 is a ligand for CXCR2 and has an inflammatory chemotaxic activity for neutrophils expressing CXCR2. Danirixin, a selective antagonist of CXCR2, might have a potential for preventing ACS. In contrast to CXCL3+ IL1B+ inflammatory macrophages (My.2), our data suspected C1Q+ TREM2+ fibrotic macrophages (My.1) function as plaque-stabilizing macrophages by inducing fibrosis, which was also discussed in the previous article.1Our study has several limitations. It was difficult to obtain sufficient cell numbers because of the small sample size. Medication exposure was different between patients with CCS and ACS, which might affect the immune cell types. The CCS or ACS plaques were pooled without differential labeling cells of each patient. Nonetheless, for the first time, we revealed the immune landscape of myeloid cells in coronary culprit plaques. We observed a unique compositional difference in myeloid cells: C100A8/9/12+ monocytes (My.3), CXCL3+ IL1B+ inflammatory macrophages (My.2), and mast cells (My.4) were detected only in the ACS plaques, suggesting these cells as potential therapeutic targets for preventing ACS.Article InformationAcknowledgmentsThe authors acknowledge Japan Research Activity Support Inc for setting up pipelines for single-cell RNA sequencing analysis and Genble Inc for constructing the single-cell RNA libraries.Sources of FundingThis work was supported by the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research grant Nos. 20K17152 (T.E.), 20H03676 (K.H.), 19H03653 (T.Y.), 20K21603 (T.Y.), 18H05429 (T.F.), and 21H04812 (T.F.); the Japan Agency for Medical Research and Development (18069370 [T.Y.], JP21gm0910012 [T.F], and JP21wm0425001 [T.F.]); a Grant for Clinical Research of the Japanese Circulation Society (T.E.); the Kowa Life Science Foundation (T.E); and the MSD Life Science Foundation (T.E.).Disclosures None.Footnotes*T. Emoto and H. Yamamoto contributed equally.For Sources of Funding and Disclosures, see page 1436.https://www.ahajournals.org/journal/circRegistration: URL: https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000046521; Unique identifier: UMIN 000040747.Correspondence to: Tomoya Yamashita, MD, PhD, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 6500017, Japan. Email [email protected]kobe-u.ac.jpReferences1. Depuydt MAC, Prange KHM, Slenders L, Örd T, Elbersen D, Boltjes A, de Jager SCA, Asselbergs FW, de Borst GJ, Aavik E, et al.. Microanatomy of the human atherosclerotic plaque by single-cell transcriptomics.Circ Res. 2020; 127:1437–1455. doi: 10.1161/CIRCRESAHA.120.316770LinkGoogle Scholar2. Sigala F, Oikonomou E, Antonopoulos AS, Galyfos G, Tousoulis D. Coronary versus carotid artery plaques. Similarities and differences regarding biomarkers morphology and prognosis.Curr Opin Pharmacol. 2018; 39:9–18. doi: 10.1016/j.coph.2017.11.010CrossrefMedlineGoogle Scholar3. Mulder K, Patel AA, Kong WT, Piot C, Halitzki E, Dunsmore G, Khalilnezhad S, Irac SE, Dubuisson A, Chevrier M, et al.. Cross-tissue single-cell landscape of human monocytes and macrophages in health and disease.Immunity. 2021; 54:1883–1900.e5. doi: 10.1016/j.immuni.2021.07.007CrossrefMedlineGoogle Scholar4. Ramachandran P, Dobie R, Wilson-Kanamori JR, Dora EF, Henderson BEP, Luu NT, Portman JR, Matchett KP, Brice M, Marwick JA, et al.. Resolving the fibrotic niche of human liver cirrhosis at single-cell level.Nature. 2019; 575:512–518. doi: 10.1038/s41586-019-1631-3CrossrefMedlineGoogle Scholar5. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, et al.; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease.N Engl J Med. 2017; 377:1119–1131. doi: 10.1056/NEJMoa1707914CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By 江本 拓, 山下 智 and 平田 健 (2022) 急性冠症候群を引き起こすプラークのシングルセル解析, Journal of JCS Cardiologists, 10.1253/jjcsc.31.0_11, 31:0, (11-16), . May 3, 2022Vol 145, Issue 18 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.121.058414PMID: 35500048 Originally publishedMay 2, 2022 Keywordshuman coronary plaqueacute coronary syndromesingle-cell RNA sequencingPDF download Advertisement SubjectsCoronary Artery Disease" @default.
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