{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T16:13:36Z","timestamp":1776442416224,"version":"3.51.2"},"reference-count":56,"publisher":"American Physiological Society","issue":"1","funder":[{"DOI":"10.13039\/501100001659","name":"German Research Foundation","doi-asserted-by":"crossref","award":["SFB 1116"],"award-info":[{"award-number":["SFB 1116"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"published-print":{"date-parts":[[2019,7,1]]},"abstract":"<jats:p>Although the cardioprotective effect of adenosine is undisputed, the role of the adenosine A<jats:sub>2b<\/jats:sub>receptor (A<jats:sub>2b<\/jats:sub>R) in ischemic cardiac remodeling is not defined. In this study we aimed to unravel the role A<jats:sub>2b<\/jats:sub>R plays in modulating the immune response and the healing mechanisms after myocardial infarction. Genetic and pharmacological (PSB603) inactivation of A<jats:sub>2b<\/jats:sub>R as well as activation of A<jats:sub>2b<\/jats:sub>R with BAY60-6583 does not alter cardiac remodeling of the infarcted (50-min left anterior descending artery occlusion\/reperfusion) murine heart. Flow cytometry of immune cell subsets identified a significant increase in B cells, NK cells, CD8 and CD4 T cells, as well as FoxP3-expressing regulatory T cells in the injured heart in A<jats:sub>2b<\/jats:sub>R-deficient mice. Analysis of T-cell function revealed that expression and secretion of interleukin (IL)-2, interferon (IFN)\u03b3, and tumor necrosis factor (TNF)\u03b1 by T cells is under A<jats:sub>2b<\/jats:sub>R control. In addition, we found substantial cellular heterogeneity in the response of immune cells and cardiomyocytes to A<jats:sub>2b<\/jats:sub>R deficiency: while in the absence of A<jats:sub>2b<\/jats:sub>R, expression of IL-6 was greatly reduced in cardiomyocytes and immune cells except T cells, and expression of IL-1\u03b2 was strongly reduced in cardiomyocytes, granulocytes, and B cells as determined by quantitative PCR. Our findings indicate that A<jats:sub>2b<\/jats:sub>R signaling in the ischemic heart triggers substantial changes in cardiac immune cell composition of the lymphoid lineage and induces a profound cell type-specific downregulation of IL-6 and IL-1\u03b2. This suggests the presence of a targetable adenosine\u2013A<jats:sub>2b<\/jats:sub>R\u2013IL-6-axis triggered by adenosine formed by the ischemic heart.<\/jats:p><jats:p>NEW &amp; NOTEWORTHY Genetic deletion and pharmacological inactivation\/activation of A<jats:sub>2b<\/jats:sub>R does not alter cardiac remodeling after MI but is associated by compensatory upregulation of various pro- and anti-inflammatory immune cell subsets (B cells, NK cells, CD8 and CD4 T cells, regulatory T cells). In the inflamed heart, A<jats:sub>2b<\/jats:sub>R modulates the expression of IL-2, IFN\u03b3, TNF\u03b1 in T cells and of IL-6 in cardiomyocytes, monocytes, granulocytes and B cells. This suggests an important adenosine\u2013IL-6 axis, which is controlled by A<jats:sub>2b<\/jats:sub>R via local adenosine.<\/jats:p>","DOI":"10.1152\/ajpheart.00029.2019","type":"journal-article","created":{"date-parts":[[2019,5,3]],"date-time":"2019-05-03T14:16:06Z","timestamp":1556892966000},"page":"H190-H200","source":"Crossref","is-referenced-by-count":13,"title":["A<sub>2b<\/sub>R-dependent signaling alters immune cell composition and enhances IL-6 formation in the ischemic heart"],"prefix":"10.1152","volume":"317","author":[{"given":"Christina","family":"Alter","sequence":"first","affiliation":[{"name":"Department of Molecular Cardiology, University D\u00fcsseldorf, Medical Faculty, D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaoping","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Molecular Cardiology, University D\u00fcsseldorf, Medical Faculty, D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Fl\u00f6gel","sequence":"additional","affiliation":[{"name":"Department of Molecular Cardiology, University D\u00fcsseldorf, Medical Faculty, D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00fcrgen","family":"Scheller","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Biology II, University D\u00fcsseldorf, Medical Faculty, Heinrich-Heine University, D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00fcrgen","family":"Schrader","sequence":"additional","affiliation":[{"name":"Department of Molecular Cardiology, University D\u00fcsseldorf, Medical Faculty, D\u00fcsseldorf, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"24","reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s11302-015-9460-9"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0034730"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.113.300180"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.023365"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00511.2010"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nri2873"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2174\/157339912803529878"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00527.2010"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2010.090759"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.669697"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.25043"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/nature08296"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030891"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00558.x"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1097\/HCO.0000000000000158"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s003950070026"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1007\/s00395-011-0151-6"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCIMAGING.116.006025"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2013.00085"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-90808-3_17"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201601307R"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.24423"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/S0736-5748(00)00026-5"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3153"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.2131\/jts.39.191"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2014.00295"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1097\/ALN.0b013e318255793c"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.7.1.273"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1809695115"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-385526-8.00004-7"},{"key":"B31","first-page":"705","volume":"56","author":"Linden J","year":"1999","journal-title":"Mol Pharmacol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2010.08.015"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.098293"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2018.06.042"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/414916a"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2018.01.001"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehy310"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.101.15.1767"},{"key":"B39","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.4049\/jimmunol.155.3.1151","volume":"155","author":"Sakaguchi S","year":"1995","journal-title":"J Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2011.01.034"},{"key":"B41","doi-asserted-by":"crossref","first-page":"549","DOI":"10.4049\/jimmunol.142.2.549","volume":"142","author":"Sironi M","year":"1989","journal-title":"J Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.4161\/chan.5.3.15765"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2016.00037"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/585297"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.111.191288"},{"key":"B46","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1182\/blood.V75.6.1305.1305","volume":"75","author":"Tosato G","year":"1990","journal-title":"Blood"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.630087"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1103721"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.115.303895"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100117"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2009.08.009"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1172\/JCI27933"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.106.649244"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2016.02.003"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2013.10.023"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3284"}],"container-title":["American Journal of Physiology-Heart and Circulatory Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajpheart.00029.2019","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,16]],"date-time":"2023-09-16T08:02:26Z","timestamp":1694851346000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajpheart.00029.2019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,1]]},"references-count":56,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,7,1]]}},"alternative-id":["10.1152\/ajpheart.00029.2019"],"URL":"https:\/\/doi.org\/10.1152\/ajpheart.00029.2019","relation":{},"ISSN":["0363-6135","1522-1539"],"issn-type":[{"value":"0363-6135","type":"print"},{"value":"1522-1539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,1]]}}}