{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T04:49:21Z","timestamp":1760244561757,"version":"build-2065373602"},"reference-count":37,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T00:00:00Z","timestamp":1672358400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["NS110378"],"award-info":[{"award-number":["NS110378"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Elabela is a component of the apelinergic system and may exert a cardioprotective role by regulating the innate immune responses. Innate lymphoid cells (ILCs) have a significant role in initiating and progressing immune-inflammatory responses. While ILCs have been intensively investigated during the last decade, little is known about their relationship with the apelinergic system and their cardiac diversity in a gender-based paradigm. In this study, we investigated the polarization of cardiac ILCs by Elabela in males versus females in a mouse model. Using flow cytometry and immunohistochemistry analyses, we showed a potential interplay between Elabela and cardiac ILCs and whether such interactions depend on sexual dimorphism. Our findings showed, for the first time, that Elabela is expressed by cardiac ILCs, and its expression is higher in females\u2019 ILC class 3 (ILC3s) compared to males. Females had higher frequencies of ILC1s, and Elabela was able to suppress T-cell activation and the expression of co-stimulatory CD28 in a mixed lymphocyte reaction assay (MLR). In conclusion, our results suggest, for the first time, a protective role for Elabela through its interplay with ILCs and that it can be used as an immunotherapeutic target in the treatment of cardiovascular disorders in a gender-based fashion.<\/jats:p>","DOI":"10.3390\/cimb45010017","type":"journal-article","created":{"date-parts":[[2023,1,2]],"date-time":"2023-01-02T04:56:27Z","timestamp":1672635387000},"page":"223-232","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sexual Dimorphism in the Polarization of Cardiac ILCs through Elabela"],"prefix":"10.3390","volume":"45","author":[{"given":"\u00c9vila Lopes","family":"Salles","sequence":"first","affiliation":[{"name":"Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2907-2414","authenticated-orcid":false,"given":"Sahar","family":"Emami Naeini","sequence":"additional","affiliation":[{"name":"Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bidhan","family":"Bhandari","sequence":"additional","affiliation":[{"name":"Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hesam","family":"Khodadadi","sequence":"additional","affiliation":[{"name":"Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edie","family":"Threlkeld","sequence":"additional","affiliation":[{"name":"Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sholeh","family":"Rezaee","sequence":"additional","affiliation":[{"name":"Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Meeks","sequence":"additional","affiliation":[{"name":"Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Avery","family":"Meeks","sequence":"additional","affiliation":[{"name":"Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aderemi","family":"Awe","sequence":"additional","affiliation":[{"name":"Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ahmed","family":"El-Marakby","sequence":"additional","affiliation":[{"name":"Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jack C.","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei P.","family":"Wang","sequence":"additional","affiliation":[{"name":"Medicinal Cannabis of Georgia LLC, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3144-2288","authenticated-orcid":false,"given":"Babak","family":"Baban","sequence":"additional","affiliation":[{"name":"Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6472","DOI":"10.1002\/jcp.26492","article-title":"Biological functions of Elabela, a novel endogenous ligand of APJ receptor","volume":"233","author":"Xu","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/j.devcel.2013.11.002","article-title":"ELABELA: A hormone essential for heart development signals via the apelin receptor","volume":"27","author":"Chng","year":"2013","journal-title":"Dev. Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1006\/bbrc.1998.9489","article-title":"Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor","volume":"251","author":"Tatemoto","year":"1998","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1080\/10641963.2019.1619756","article-title":"Declined circulating Elabela levels in patients with essential hypertension and its association with impaired vascular function: A preliminary study","volume":"42","author":"Li","year":"2020","journal-title":"Clin. Exp. Hypertens."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.freeradbiomed.2022.01.020","article-title":"Elabela alleviates ferroptosis, myocardial remodeling, fibrosis and heart dysfunction in hypertensive mice by modulating the IL-6\/STAT3\/GPX4 signaling","volume":"181","author":"Zhang","year":"2022","journal-title":"Free Radic. Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1007\/s10741-020-09957-5","article-title":"The Elabela-APJ axis: A promising therapeutic target for heart failure","volume":"26","author":"Ma","year":"2021","journal-title":"Heart Fail. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2573","DOI":"10.1038\/s41401-022-00875-w","article-title":"Chronic infusion of ELABELA alleviates vascular remodeling in spontaneously hypertensive rats via anti-inflammatory, anti-oxidative and anti-proliferative effects","volume":"43","author":"Ye","year":"2022","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1111\/imr.12407","article-title":"Innate lymphoid cells in secondary lymphoid organs","volume":"271","author":"Mebius","year":"2016","journal-title":"Immunol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1038\/nature14189","article-title":"The biology of innate lymphoid cells","volume":"517","author":"Artis","year":"2015","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2640","DOI":"10.1172\/JCI124617","article-title":"The balance of power: Innate lymphoid cells in tissue inflammation and repair","volume":"129","author":"Castellanos","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/j.cell.2018.07.017","article-title":"Innate Lymphoid Cells: 10 Years On","volume":"174","author":"Vivier","year":"2018","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"405","DOI":"10.3389\/fimmu.2019.00405","article-title":"Physiological Regulation of Innate Lymphoid Cells","volume":"10","author":"Jacquelot","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.ejphar.2017.04.030","article-title":"Innate lymphoid cells in atherosclerosis","volume":"816","author":"Engelbertsen","year":"2017","journal-title":"Eur. J. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"758272","DOI":"10.3389\/fimmu.2021.758272","article-title":"Innate Lymphoid Cells and Myocardial Infarction","volume":"12","author":"Yang","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"15781","DOI":"10.1038\/ncomms15781","article-title":"Type-2 innate lymphoid cells control the development of atherosclerosis in mice","volume":"8","author":"Newland","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"755","DOI":"10.2217\/imt.14.37","article-title":"Peptides and peptidomimetics as immunomodulators","volume":"6","author":"Gokhale","year":"2014","journal-title":"Immunotherapy"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/nrneph.2017.189","article-title":"Sex-specific differences in hypertension and associated cardiovascular disease","volume":"14","author":"Colafella","year":"2018","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1007\/s12016-017-8648-x","article-title":"Sexual Dimorphism in Innate Immunity","volume":"56","author":"Jaillon","year":"2019","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"698121","DOI":"10.3389\/fimmu.2021.698121","article-title":"Sexual Dimorphism and Gender in Infectious Diseases","volume":"12","author":"Gay","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"802","DOI":"10.3389\/fimmu.2020.00802","article-title":"Unique Phenotypes of Heart Resident Type 2 Innate Lymphoid Cells","volume":"11","author":"Deng","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Enriquez, J., Mims, B.M.D., Trasti, S., Furr, K.L., and Grisham, M.B. (2020). Genomic, microbial and environmental standardization in animal experimentation limiting immunological discovery. BMC Immunol., 21.","DOI":"10.1186\/s12865-020-00380-x"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1002\/eji.201545598","article-title":"Group 3 innate lymphoid cells (ILC3s): Origin, differentiation, and plasticity in humans and mice","volume":"45","author":"Montaldo","year":"2015","journal-title":"Eur. J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"979","DOI":"10.4254\/wjh.v9.i23.979","article-title":"Innate lymphoid cells in tissue homeostasis and diseases","volume":"9","author":"Ignacio","year":"2017","journal-title":"World J. Hepatol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"116","DOI":"10.3389\/fimmu.2020.00116","article-title":"Immunoregulatory Sensory Circuits in Group 3 Innate Lymphoid Cell (ILC3) Function and Tissue Homeostasis","volume":"11","author":"Domingues","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s10989-018-9707-8","article-title":"ELABELA (ELA) Peptide Exerts Cardioprotection Against Myocardial Infarction by Targeting Oxidative Stress and the Improvement of Heart Function","volume":"25","author":"Rakhshan","year":"2019","journal-title":"Int. J. Pept. Res. Ther."},{"key":"ref_26","first-page":"4467","article-title":"Elabela alleviates myocardial ischemia reperfusion-induced apoptosis, fibrosis and mitochondrial dysfunction through PI3K\/AKT signaling","volume":"12","author":"Yu","year":"2020","journal-title":"Am. J. Transl. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1111\/imm.12639","article-title":"Innate lymphoid cell regulation of adaptive immunity","volume":"149","author":"Withers","year":"2016","journal-title":"Immunology"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1038\/nature12240","article-title":"Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria","volume":"498","author":"Hepworth","year":"2013","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/s41577-019-0194-8","article-title":"Functional interactions between innate lymphoid cells and adaptive immunity","volume":"19","author":"Sonnenberg","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"590964","DOI":"10.3389\/fimmu.2020.590964","article-title":"CD28 Autonomous Signaling Orchestrates IL-22 Expression and IL-22-Regulated Epithelial Barrier Functions in Human T Lymphocytes","volume":"11","author":"Kunkl","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1007\/s10735-021-10011-3","article-title":"Elabela prevents angiotensin II-induced apoptosis and inflammation in rat aortic adventitial fibroblasts via the activation of FGF21-ACE2 signaling","volume":"52","author":"Song","year":"2021","journal-title":"J. Mol. Histol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1034\/j.1600-065X.2003.00008.x","article-title":"The PI-3 kinase\/Akt pathway and T cell activation: Pleiotropic pathways downstream of PIP3","volume":"192","author":"Kane","year":"2003","journal-title":"Immunol. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1089\/jwh.2018.7618","article-title":"Clinical Presentation and Laboratory Findings in Men Versus Women with Myocarditis","volume":"29","author":"Patriki","year":"2020","journal-title":"J. Womens Health"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1016\/j.it.2020.03.002","article-title":"Helper-like Innate Lymphoid Cells in Humans and Mice","volume":"41","author":"Guia","year":"2020","journal-title":"Trends Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/j.tips.2015.06.002","article-title":"Apelin, Elabela\/Toddler, and biased agonists as novel therapeutic agents in the cardiovascular system","volume":"36","author":"Yang","year":"2015","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Kino, T., Khan, M., and Mohsin, S. (2020). The Regulatory Role of T Cell Responses in Cardiac Remodeling Following Myocardial Infarction. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21145013"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Baban, B., Liu, J.Y., Qin, X., Weintraub, N.L., and Mozaffari, M.S. (2015). Upregulation of Programmed Death-1 and Its Ligand in Cardiac Injury Models: Interaction with GADD153. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124059"}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/45\/1\/17\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:56:29Z","timestamp":1760147789000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/45\/1\/17"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,30]]},"references-count":37,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["cimb45010017"],"URL":"https:\/\/doi.org\/10.3390\/cimb45010017","relation":{},"ISSN":["1467-3045"],"issn-type":[{"type":"electronic","value":"1467-3045"}],"subject":[],"published":{"date-parts":[[2022,12,30]]}}}