{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T14:38:34Z","timestamp":1787755114137,"version":"build-2784847793"},"reference-count":72,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T00:00:00Z","timestamp":1700870400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T00:00:00Z","timestamp":1700870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Commun Biol"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The source and roles of fibroblasts and T-cells during maladaptive remodeling and myocardial fibrosis in the setting of pulmonary arterial hypertension (PAH) have been long debated. We demonstrate, using single-cell mass cytometry, a subpopulation of endogenous human cardiac fibroblasts expressing increased levels of CD4, a helper T-cell marker, in addition to myofibroblast markers distributed in human fibrotic RV tissue, interstitial and perivascular lesions in SUGEN\/Hypoxia (SuHx) rats, and fibroblasts labeled with pdgfr\u03b1 CreERt2\/+ in R26R-tdTomato mice. Recombinant IL-1\u03b2 increases IL-1R, CCR2 receptor expression, modifies the secretome, and differentiates cardiac fibroblasts to form CD68-positive cell clusters. IL-1\u03b2 also activates stemness markers, such as NANOG and SOX2, and genes involved in dedifferentiation, lymphoid cell function and metabolic reprogramming. IL-1\u03b2 induction of lineage traced primary mouse cardiac fibroblasts causes these cells to lose their fibroblast identity and acquire an immune phenotype. Our results identify IL-1\u03b2 induced immune-competency in human cardiac fibroblasts and suggest that fibroblast secretome modulation may constitute a therapeutic approach to PAH and other diseases typified by inflammation and fibrotic remodeling.<\/jats:p>","DOI":"10.1038\/s42003-023-05463-0","type":"journal-article","created":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T04:22:04Z","timestamp":1700886124000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["IL-1\u03b2-mediated adaptive reprogramming of endogenous human cardiac fibroblasts to cells with immune features during fibrotic remodeling"],"prefix":"10.1038","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9482-9183","authenticated-orcid":false,"given":"Jamila H.","family":"Siamwala","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6250-8315","authenticated-orcid":false,"given":"Francesco S.","family":"Pagano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3987-0647","authenticated-orcid":false,"given":"Patrycja M.","family":"Dubielecka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malina J.","family":"Ivey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose Pedro","family":"Guirao-Abad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6174-8723","authenticated-orcid":false,"given":"Sonja","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haley","family":"Granston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Yun","family":"Jeong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Rounds","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Onur","family":"Kanisicak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2006-7678","authenticated-orcid":false,"given":"Sakthivel","family":"Sadayappan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Gilbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,11,25]]},"reference":[{"key":"5463_CR1","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.1016\/j.jacc.2009.04.009","volume":"54","author":"RM Tuder","year":"2009","unstructured":"Tuder, R. M. et al. Development and pathology of pulmonary hypertension. J. Am. Coll. Cardiol. 54, S3\u2013S9 (2009).","journal-title":"J. Am. Coll. Cardiol."},{"key":"5463_CR2","doi-asserted-by":"publisher","first-page":"591","DOI":"10.1161\/HYPERTENSIONAHA.109.131243","volume":"54","author":"SA Chang","year":"2009","unstructured":"Chang, S. A. et al. Effect of rosuvastatin on cardiac remodeling, function, and progression to heart failure in hypertensive heart with established left ventricular hypertrophy. Hypertension 54, 591\u2013597 (2009).","journal-title":"Hypertension"},{"key":"5463_CR3","doi-asserted-by":"publisher","first-page":"2711","DOI":"10.4049\/jimmunol.1100479","volume":"187","author":"M Li","year":"2011","unstructured":"Li, M. et al. Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension. J. Immunol. 187, 2711\u20132722 (2011).","journal-title":"J. Immunol."},{"key":"5463_CR4","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1093\/cvr\/cvs115","volume":"95","author":"D Gomez","year":"2012","unstructured":"Gomez, D. & Owens, G. K. Smooth muscle cell phenotypic switching in atherosclerosis. Cardiovasc. Res. 95, 156\u2013164 (2012).","journal-title":"Cardiovasc. Res."},{"key":"5463_CR5","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1183\/13993003.00996-2016","volume":"48","author":"J Gomez-Arroyo","year":"2016","unstructured":"Gomez-Arroyo, J., Abbate, A. & Voelkel, N. F. Pulmonary arterial hypertension and the Enigma code of smouldering inflammation. Eur. Respir. J. 48, 305\u2013307 (2016).","journal-title":"Eur. Respir. J."},{"key":"5463_CR6","doi-asserted-by":"crossref","unstructured":"Chen, B. & Frangogiannis, N. G. Immune cells in repair of the infarcted myocardium. Microcirculation 24, e12305 (2017).","DOI":"10.1111\/micc.12305"},{"key":"5463_CR7","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1161\/CIRCRESAHA.112.269035","volume":"110","author":"TM Jayawardena","year":"2012","unstructured":"Jayawardena, T. M. et al. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ. Res. 110, 1465\u20131473 (2012).","journal-title":"Circ. Res."},{"key":"5463_CR8","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1146\/annurev.pharmtox.45.120403.095802","volume":"45","author":"RD Brown","year":"2005","unstructured":"Brown, R. D., Ambler, S. K., Mitchell, M. D. & Long, C. S. The cardiac fibroblast: therapeutic target in myocardial remodeling and failure. Annu. Rev. Pharm. Toxicol. 45, 657\u2013687 (2005).","journal-title":"Annu. Rev. Pharm. Toxicol."},{"key":"5463_CR9","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1161\/CIRCRESAHA.109.209809","volume":"105","author":"CA Souders","year":"2009","unstructured":"Souders, C. A., Bowers, S. L. & Baudino, T. A. Cardiac fibroblast: the renaissance cell. Circ. Res. 105, 1164\u20131176 (2009).","journal-title":"Circ. Res."},{"key":"5463_CR10","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1161\/CIRCULATIONAHA.118.036065","volume":"139","author":"SS Bansal","year":"2019","unstructured":"Bansal, S. S. et al. Dysfunctional and proinflammatory regulatory T-lymphocytes are essential for adverse cardiac remodeling in ischemic cardiomyopathy. Circulation 139, 206\u2013221 (2019).","journal-title":"Circulation"},{"key":"5463_CR11","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1016\/j.carpath.2005.05.004","volume":"14","author":"T Yano","year":"2005","unstructured":"Yano, T. et al. Intracardiac fibroblasts, but not bone marrow derived cells, are the origin of myofibroblasts in myocardial infarct repair. Cardiovasc. Pathol. 14, 241\u2013246 (2005).","journal-title":"Cardiovasc. Pathol."},{"key":"5463_CR12","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1161\/CIRCRESAHA.110.231910","volume":"107","author":"EM Zeisberg","year":"2010","unstructured":"Zeisberg, E. M. & Kalluri, R. Origins of cardiac fibroblasts. Circ. Res. 107, 1304\u20131312 (2010).","journal-title":"Circ. Res."},{"key":"5463_CR13","doi-asserted-by":"publisher","first-page":"870","DOI":"10.1002\/dvg.20750","volume":"49","author":"A Acharya","year":"2011","unstructured":"Acharya, A., Baek, S. T., Banfi, S., Eskiocak, B. & Tallquist, M. D. Efficient inducible Cre-mediated recombination in Tcf21 cell lineages in the heart and kidney. Genesis 49, 870\u2013877 (2011).","journal-title":"Genesis"},{"key":"5463_CR14","doi-asserted-by":"publisher","first-page":"1906","DOI":"10.1161\/CIRCRESAHA.116.308643","volume":"118","author":"H Kaur","year":"2016","unstructured":"Kaur, H. et al. Targeted ablation of periostin-expressing activated fibroblasts prevents adverse cardiac remodeling in mice. Circ. Res. 118, 1906\u20131917 (2016).","journal-title":"Circ. Res."},{"key":"5463_CR15","doi-asserted-by":"publisher","first-page":"2127","DOI":"10.1172\/JCI98215","volume":"128","author":"X Fu","year":"2018","unstructured":"Fu, X. et al. Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart. J. Clin. Invest. 128, 2127\u20132143 (2018).","journal-title":"J. Clin. Invest."},{"key":"5463_CR16","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1161\/CIRCULATIONAHA.113.007394","volume":"131","author":"N Sayed","year":"2015","unstructured":"Sayed, N. et al. Transdifferentiation of human fibroblasts to endothelial cells: role of innate immunity. Circulation 131, 300\u2013309 (2015).","journal-title":"Circulation"},{"key":"5463_CR17","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1161\/CIRCRESAHA.115.303895","volume":"115","author":"J Weirather","year":"2014","unstructured":"Weirather, J. et al. Foxp3+ CD4+ T cells improve healing after myocardial infarction by modulating monocyte\/macrophage differentiation. Circ. Res. 115, 55\u201367 (2014).","journal-title":"Circ. Res."},{"key":"5463_CR18","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1097\/CCM.0b013e3181de8bd3","volume":"38","author":"C Dewachter","year":"2010","unstructured":"Dewachter, C. et al. Activation of apoptotic pathways in experimental acute afterload-induced right ventricular failure. Crit. Care Med. 38, 1405\u20131413 (2010).","journal-title":"Crit. Care Med."},{"key":"5463_CR19","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1038\/nature24676","volume":"552","author":"S Schafer","year":"2017","unstructured":"Schafer, S. et al. IL-11 is a crucial determinant of cardiovascular fibrosis. Nature 552, 110\u2013115 (2017).","journal-title":"Nature"},{"key":"5463_CR20","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.yjmcc.2006.05.011","volume":"41","author":"JA Watts","year":"2006","unstructured":"Watts, J. A., Zagorski, J., Gellar, M. A., Stevinson, B. G. & Kline, J. A. Cardiac inflammation contributes to right ventricular dysfunction following experimental pulmonary embolism in rats. J. Mol. Cell Cardiol. 41, 296\u2013307 (2006).","journal-title":"J. Mol. Cell Cardiol."},{"key":"5463_CR21","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1097\/FJC.0b013e3181b2b699","volume":"54","author":"JA Watts","year":"2009","unstructured":"Watts, J. A., Gellar, M. A., Stuart, L. K., Obraztsova, M. & Kline, J. A. Proinflammatory events in right ventricular damage during pulmonary embolism: effects of treatment with ketorolac in rats. J. Cardiovasc. Pharm. 54, 246\u2013252 (2009).","journal-title":"J. Cardiovasc. Pharm."},{"key":"5463_CR22","doi-asserted-by":"publisher","first-page":"e69470","DOI":"10.1371\/journal.pone.0069470","volume":"8","author":"A Belhaj","year":"2013","unstructured":"Belhaj, A. et al. Heme oxygenase-1 and inflammation in experimental right ventricular failure on prolonged overcirculation-induced pulmonary hypertension. PLoS ONE 8, e69470 (2013).","journal-title":"PLoS ONE"},{"key":"5463_CR23","doi-asserted-by":"publisher","first-page":"915","DOI":"10.1183\/09031936.00151313","volume":"43","author":"JL Cracowski","year":"2014","unstructured":"Cracowski, J. L. et al. Proinflammatory cytokine levels are linked to death in pulmonary arterial hypertension. Eur. Respir. J. 43, 915\u2013917 (2014).","journal-title":"Eur. Respir. J."},{"key":"5463_CR24","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1016\/j.cyto.2018.09.021","volume":"113","author":"J Sandstedt","year":"2019","unstructured":"Sandstedt, J. et al. Human cardiac fibroblasts isolated from patients with severe heart failure are immune-competent cells mediating an inflammatory response. Cytokine 113, 319\u2013325 (2019).","journal-title":"Cytokine"},{"key":"5463_CR25","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1096\/fj.00-0343com","volume":"15","author":"L Taraseviciene-Stewart","year":"2001","unstructured":"Taraseviciene-Stewart, L. et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J. 15, 427\u2013438 (2001).","journal-title":"FASEB J."},{"key":"5463_CR26","doi-asserted-by":"publisher","first-page":"434","DOI":"10.4103\/2045-8932.105031","volume":"2","author":"MR Nicolls","year":"2012","unstructured":"Nicolls, M. R. et al. New models of pulmonary hypertension based on VEGF receptor blockade-induced endothelial cell apoptosis. Pulm. Circ. 2, 434\u2013442 (2012).","journal-title":"Pulm. Circ."},{"key":"5463_CR27","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1161\/01.RES.0000117070.86556.9F","volume":"94","author":"AM Kapoun","year":"2004","unstructured":"Kapoun, A. M. et al. B-type natriuretic peptide exerts broad functional opposition to transforming growth factor-beta in primary human cardiac fibroblasts: fibrosis, myofibroblast conversion, proliferation, and inflammation. Circ. Res. 94, 453\u2013461 (2004).","journal-title":"Circ. Res."},{"key":"5463_CR28","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1161\/CIRCRESAHA.115.303794","volume":"115","author":"SR Ali","year":"2014","unstructured":"Ali, S. R. et al. Developmental heterogeneity of cardiac fibroblasts does not predict pathological proliferation and activation. Circ. Res. 115, 625\u2013635 (2014).","journal-title":"Circ. Res."},{"key":"5463_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms12260","volume":"7","author":"O Kanisicak","year":"2016","unstructured":"Kanisicak, O. et al. Genetic lineage tracing defines myofibroblast origin and function in the injured heart. Nat. Commun. 7, 12260 (2016).","journal-title":"Nat. Commun."},{"key":"5463_CR30","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1161\/CIRCRESAHA.115.307778","volume":"118","author":"AR Pinto","year":"2016","unstructured":"Pinto, A. R. et al. Revisiting cardiac cellular composition. Circ. Res. 118, 400\u2013409 (2016).","journal-title":"Circ. Res."},{"key":"5463_CR31","doi-asserted-by":"publisher","first-page":"2921","DOI":"10.1172\/JCI74783","volume":"124","author":"T Moore-Morris","year":"2014","unstructured":"Moore-Morris, T. et al. Resident fibroblast lineages mediate pressure overload-induced cardiac fibrosis. J. Clin. Invest. 124, 2921\u20132934 (2014).","journal-title":"J. Clin. Invest."},{"key":"5463_CR32","doi-asserted-by":"publisher","first-page":"952","DOI":"10.1038\/nm1613","volume":"13","author":"EM Zeisberg","year":"2007","unstructured":"Zeisberg, E. M. et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat. Med. 13, 952\u2013961 (2007).","journal-title":"Nat. Med."},{"key":"5463_CR33","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1073\/pnas.1017547108","volume":"108","author":"CH Osterreicher","year":"2011","unstructured":"Osterreicher, C. H. et al. Fibroblast-specific protein 1 identifies an inflammatory subpopulation of macrophages in the liver. Proc. Natl Acad. Sci. USA 108, 308\u2013313 (2011).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"5463_CR34","doi-asserted-by":"publisher","first-page":"H1363","DOI":"10.1152\/ajpheart.00395.2013","volume":"305","author":"P Kong","year":"2013","unstructured":"Kong, P., Christia, P., Saxena, A., Su, Y. & Frangogiannis, N. G. Lack of specificity of fibroblast-specific protein 1 in cardiac remodeling and fibrosis. Am. J. Physiol. Heart Circ. Physiol. 305, H1363\u2013H1372 (2013).","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"5463_CR35","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/s11926-018-0725-5","volume":"20","author":"KS Smigiel","year":"2018","unstructured":"Smigiel, K. S. & Parks, W. C. Macrophages, wound healing, and fibrosis: recent insights. Curr. Rheumatol. Rep. 20, 17 (2018).","journal-title":"Curr. Rheumatol. Rep."},{"key":"5463_CR36","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1161\/CIRCRESAHA.118.314028","volume":"124","author":"G Bajpai","year":"2019","unstructured":"Bajpai, G. et al. Tissue resident CCR2\u2212 and CCR2+ cardiac macrophages differentially orchestrate monocyte recruitment and fate specification following myocardial injury. Circ. Res. 124, 263\u2013278 (2019).","journal-title":"Circ. Res."},{"key":"5463_CR37","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1161\/CIRCULATIONAHA.119.045401","volume":"142","author":"NR Tucker","year":"2020","unstructured":"Tucker, N. R. et al. Transcriptional and cellular diversity of the human heart. Circulation 142, 466\u2013482 (2020).","journal-title":"Circulation"},{"key":"5463_CR38","doi-asserted-by":"publisher","first-page":"110322","DOI":"10.1016\/j.ygeno.2022.110322","volume":"114","author":"J Wan","year":"2022","unstructured":"Wan, J. et al. Single cell study of cellular diversity and mutual communication in chronic heart failure and drug repositioning. Genomics 114, 110322 (2022).","journal-title":"Genomics"},{"key":"5463_CR39","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1016\/j.pharmthera.2013.10.007","volume":"141","author":"N Milani-Nejad","year":"2014","unstructured":"Milani-Nejad, N. & Janssen, P. M. Small and large animal models in cardiac contraction research: advantages and disadvantages. Pharm. Ther. 141, 235\u2013249 (2014).","journal-title":"Pharm. Ther."},{"key":"5463_CR40","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1093\/cvr\/cvy258","volume":"115","author":"CM Suen","year":"2019","unstructured":"Suen, C. M., Chaudhary, K. R., Deng, Y., Jiang, B. & Stewart, D. J. Fischer rats exhibit maladaptive structural and molecular right ventricular remodelling in severe pulmonary hypertension: a genetically prone model for right heart failure. Cardiovasc. Res. 115, 788\u2013799 (2019).","journal-title":"Cardiovasc. Res."},{"key":"5463_CR41","doi-asserted-by":"publisher","first-page":"1628","DOI":"10.1164\/ajrccm.151.5.7735624","volume":"151","author":"M Humbert","year":"1995","unstructured":"Humbert, M. et al. Increased interleukin-1 and interleukin-6 serum concentrations in severe primary pulmonary hypertension. Am. J. Respir. Crit. Care Med. 151, 1628\u20131631 (1995).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"5463_CR42","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1164\/rccm.201809-1631LE","volume":"199","author":"CR Trankle","year":"2019","unstructured":"Trankle, C. R. et al. IL-1 blockade reduces inflammation in pulmonary arterial hypertension and right ventricular failure: a single-arm, open-label, phase IB\/II pilot study. Am. J. Respir. Crit. Care Med. 199, 381\u2013384 (2019).","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"5463_CR43","doi-asserted-by":"publisher","first-page":"5627","DOI":"10.4049\/jimmunol.1003998","volume":"187","author":"K Hebel","year":"2011","unstructured":"Hebel, K. et al. IL-1beta and TGF-beta act antagonistically in induction and differentially in propagation of human proinflammatory precursor CD4+ T cells. J. Immunol. 187, 5627\u20135635 (2011).","journal-title":"J. Immunol."},{"key":"5463_CR44","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1007\/s00005-009-0024-y","volume":"57","author":"M Bujak","year":"2009","unstructured":"Bujak, M. & Frangogiannis, N. G. The role of IL-1 in the pathogenesis of heart disease. Arch. Immunol. Ther. Exp. 57, 165\u2013176 (2009).","journal-title":"Arch. Immunol. Ther. Exp."},{"key":"5463_CR45","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1016\/j.immuni.2009.02.007","volume":"30","author":"Y Chung","year":"2009","unstructured":"Chung, Y. et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30, 576\u2013587 (2009).","journal-title":"Immunity"},{"key":"5463_CR46","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.clim.2008.12.008","volume":"131","author":"F Deknuydt","year":"2009","unstructured":"Deknuydt, F., Bioley, G., Valmori, D. & Ayyoub, M. IL-1beta and IL-2 convert human Treg into T(H)17 cells. Clin. Immunol. 131, 298\u2013307 (2009).","journal-title":"Clin. Immunol."},{"key":"5463_CR47","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.ymeth.2015.05.008","volume":"82","author":"KE Diggins","year":"2015","unstructured":"Diggins, K. E., Ferrell, P. B. Jr & Irish, J. M. Methods for discovery and characterization of cell subsets in high dimensional mass cytometry data. Methods 82, 55\u201363 (2015).","journal-title":"Methods"},{"key":"5463_CR48","doi-asserted-by":"publisher","first-page":"886","DOI":"10.1038\/nbt.1991","volume":"29","author":"P Qiu","year":"2011","unstructured":"Qiu, P. et al. Extracting a cellular hierarchy from high-dimensional cytometry data with SPADE. Nat. Biotechnol. 29, 886\u2013891 (2011).","journal-title":"Nat. Biotechnol."},{"key":"5463_CR49","doi-asserted-by":"publisher","first-page":"2095","DOI":"10.1182\/blood.V87.6.2095.bloodjournal8762095","volume":"87","author":"CA Dinarello","year":"1996","unstructured":"Dinarello, C. A. Biologic basis for interleukin-1 in disease. Blood 87, 2095\u20132147 (1996).","journal-title":"Blood"},{"key":"5463_CR50","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1038\/ki.1995.126","volume":"47","author":"G Lonnemann","year":"1995","unstructured":"Lonnemann, G. et al. Cytokines in human renal interstitial fibrosis. I. Interleukin-1 is a paracrine growth factor for cultured fibrosis-derived kidney fibroblasts. Kidney Int. 47, 837\u2013844 (1995).","journal-title":"Kidney Int."},{"key":"5463_CR51","doi-asserted-by":"publisher","first-page":"4818","DOI":"10.1093\/nar\/22.22.4818","volume":"22","author":"MP Vincenti","year":"1994","unstructured":"Vincenti, M. P., Coon, C. I., Lee, O. & Brinckerhoff, C. E. Regulation of collagenase gene expression by IL-1 beta requires transcriptional and post-transcriptional mechanisms. Nucleic Acids Res. 22, 4818\u20134827 (1994).","journal-title":"Nucleic Acids Res."},{"key":"5463_CR52","doi-asserted-by":"publisher","first-page":"117","DOI":"10.3109\/13813455.2016.1156706","volume":"122","author":"SY Alomar","year":"2016","unstructured":"Alomar, S. Y., Gentili, A., Zaibi, M. S., Kepczynska, M. A. & Trayhurn, P. IL-1beta (interleukin-1beta) stimulates the production and release of multiple cytokines and chemokines by human preadipocytes. Arch. Physiol. Biochem. 122, 117\u2013122 (2016).","journal-title":"Arch. Physiol. Biochem."},{"key":"5463_CR53","first-page":"H330","volume":"317","author":"MJ Ivey","year":"2019","unstructured":"Ivey, M. J. et al. Platelet-derived growth factor receptor-\u03b1 is essential for cardiac fibroblast survival. Am. J. Physiol. 317, H330\u2013H344 (2019).","journal-title":"Am. J. Physiol."},{"key":"5463_CR54","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/j.yjmcc.2017.11.012","volume":"114","author":"MJ Ivey","year":"2018","unstructured":"Ivey, M. J. et al. Resident fibroblast expansion during cardiac growth and remodeling. J. Mol. Cell Cardiol. 114, 161\u2013174 (2018).","journal-title":"J. Mol. Cell Cardiol."},{"key":"5463_CR55","doi-asserted-by":"crossref","unstructured":"Kuwabara, J. T. et al. Regulation of extracellular matrix composition by fibroblasts during perinatal cardiac maturation. J. Mol. Cell. Cardiol. 169, 84\u201395 (2022).","DOI":"10.1016\/j.yjmcc.2022.05.003"},{"key":"5463_CR56","doi-asserted-by":"publisher","first-page":"32","DOI":"10.3389\/fcvm.2019.00032","volume":"6","author":"S Psarras","year":"2019","unstructured":"Psarras, S., Beis, D., Nikouli, S., Tsikitis, M. & Capetanaki, Y. Three in a box: understanding cardiomyocyte, fibroblast, and innate immune cell interactions to orchestrate cardiac repair processes. Front. Cardiovasc. Med. 6, 32 (2019).","journal-title":"Front. Cardiovasc. Med."},{"key":"5463_CR57","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1093\/cvr\/cvu062","volume":"102","author":"S Van Linthout","year":"2014","unstructured":"Van Linthout, S., Miteva, K. & Tschope, C. Crosstalk between fibroblasts and inflammatory cells. Cardiovasc. Res. 102, 258\u2013269 (2014).","journal-title":"Cardiovasc. Res."},{"key":"5463_CR58","doi-asserted-by":"publisher","first-page":"1722","DOI":"10.1161\/CIRCRESAHA.118.311362","volume":"122","author":"A Grebe","year":"2018","unstructured":"Grebe, A., Hoss, F. & Latz, E. NLRP3 inflammasome and the IL-1 pathway in atherosclerosis. Circ. Res. 122, 1722\u20131740 (2018).","journal-title":"Circ. Res."},{"key":"5463_CR59","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1183\/09031936.00159911","volume":"40","author":"A Huertas","year":"2012","unstructured":"Huertas, A. et al. Leptin and regulatory T-lymphocytes in idiopathic pulmonary arterial hypertension. Eur. Respir. J. 40, 895\u2013904 (2012).","journal-title":"Eur. Respir. J."},{"key":"5463_CR60","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1161\/CIRCRESAHA.110.236927","volume":"109","author":"R Tamosiuniene","year":"2011","unstructured":"Tamosiuniene, R. et al. Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circ. Res. 109, 867\u2013879 (2011).","journal-title":"Circ. Res."},{"key":"5463_CR61","doi-asserted-by":"publisher","first-page":"2111","DOI":"10.1161\/CIRCULATIONAHA.113.007101","volume":"129","author":"F Laroumanie","year":"2014","unstructured":"Laroumanie, F. et al. CD4+ T cells promote the transition from hypertrophy to heart failure during chronic pressure overload. Circulation 129, 2111\u20132124 (2014).","journal-title":"Circulation"},{"key":"5463_CR62","doi-asserted-by":"publisher","first-page":"10131","DOI":"10.1073\/pnas.1911497117","volume":"117","author":"B Roy","year":"2020","unstructured":"Roy, B. et al. Fibroblast rejuvenation by mechanical reprogramming and redifferentiation. Proc. Natl Acad. Sci. USA 117, 10131\u201310141 (2020).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"5463_CR63","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1038\/s41577-020-0285-6","volume":"20","author":"MG Netea","year":"2020","unstructured":"Netea, M. G. et al. Defining trained immunity and its role in health and disease. Nat. Rev. Immunol. 20, 375\u2013388 (2020).","journal-title":"Nat. Rev. Immunol."},{"key":"5463_CR64","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16466-4","volume":"11","author":"L Cui","year":"2020","unstructured":"Cui, L. et al. Activation of JUN in fibroblasts promotes pro-fibrotic programme and modulates protective immunity. Nat. Commun. 11, 2795 (2020).","journal-title":"Nat. Commun."},{"key":"5463_CR65","doi-asserted-by":"publisher","first-page":"W652","DOI":"10.1093\/nar\/gkp356","volume":"37","author":"J Xia","year":"2009","unstructured":"Xia, J., Psychogios, N., Young, N. & Wishart, D. S. MetaboAnalyst: a web server for metabolomic data analysis and interpretation. Nucleic Acids Res. 37, W652\u2013W660 (2009).","journal-title":"Nucleic Acids Res."},{"key":"5463_CR66","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1161\/CIRCRESAHA.116.309202","volume":"119","author":"M Ackers-Johnson","year":"2016","unstructured":"Ackers-Johnson, M. et al. A simplified, Langendorff-free method for concomitant isolation of viable cardiac myocytes and nonmyocytes from the adult mouse heart. Circ. Res. 119, 909\u2013920 (2016).","journal-title":"Circ. Res."},{"key":"5463_CR67","doi-asserted-by":"publisher","first-page":"2849","DOI":"10.1161\/01.CIR.88.6.2849","volume":"88","author":"FJ Villarreal","year":"1993","unstructured":"Villarreal, F. J., Kim, N. N., Ungab, G. D., Printz, M. P. & Dillmann, W. H. Identification of functional angiotensin II receptors on rat cardiac fibroblasts. Circulation 88, 2849\u20132861 (1993).","journal-title":"Circulation"},{"key":"5463_CR68","doi-asserted-by":"publisher","first-page":"2269","DOI":"10.1253\/circj.CJ-16-1003","volume":"80","author":"MJ Ivey","year":"2016","unstructured":"Ivey, M. J. & Tallquist, M. D. Defining the cardiac fibroblast. Circ. J. 80, 2269\u20132276 (2016).","journal-title":"Circ. J."},{"key":"5463_CR69","doi-asserted-by":"publisher","first-page":"e0008112","DOI":"10.1371\/journal.pntd.0008112","volume":"14","author":"Y Zhao","year":"2020","unstructured":"Zhao, Y. et al. Single cell immune profiling of dengue virus patients reveals intact immune responses to Zika virus with enrichment of innate immune signatures. PLoS Negl. Trop. Dis. 14, e0008112 (2020).","journal-title":"PLoS Negl. Trop. Dis."},{"key":"5463_CR70","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1002\/cyto.a.22625","volume":"87","author":"S Van Gassen","year":"2015","unstructured":"Van Gassen, S. et al. FlowSOM: using self-organizing maps for visualization and interpretation of cytometry data. Cytom. A 87, 636\u2013645 (2015).","journal-title":"Cytom. A"},{"key":"5463_CR71","doi-asserted-by":"publisher","first-page":"L56","DOI":"10.1152\/ajplung.00436.2016","volume":"312","author":"P Sakhatskyy","year":"2017","unstructured":"Sakhatskyy, P. et al. Double-hit mouse model of cigarette smoke priming for acute lung injury. Am. J. Physiol. Lung Cell Mol. Physiol. 312, L56\u2013L67 (2017).","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"5463_CR72","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1038\/nprot.2012.024","volume":"7","author":"M Yuan","year":"2012","unstructured":"Yuan, M., Breitkopf, S. B., Yang, X. & Asara, J. M. A positive\/negative ion-switching, targeted mass spectrometry-based metabolomics platform for bodily fluids, cells, and fresh and fixed tissue. Nat. Protoc. 7, 872\u2013881 (2012).","journal-title":"Nat. Protoc."}],"container-title":["Communications Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s42003-023-05463-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-023-05463-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s42003-023-05463-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T05:03:34Z","timestamp":1700888614000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s42003-023-05463-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,25]]},"references-count":72,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["5463"],"URL":"https:\/\/doi.org\/10.1038\/s42003-023-05463-0","relation":{},"ISSN":["2399-3642"],"issn-type":[{"value":"2399-3642","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,25]]},"assertion":[{"value":"9 May 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 October 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 November 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"S.S. provided consulting and collaborative research studies to the Leducq Foundation (CURE-PLAN), Red Saree Inc., Greater Cincinnati Tamil Sangam, AavantiBio, Pfizer, Novo Nordisk, AstraZeneca, MyoKardia, Merck and Amgen. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1200"}}