{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T20:45:53Z","timestamp":1785789953729,"version":"3.56.0"},"reference-count":50,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T00:00:00Z","timestamp":1700438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Age and sex are prominent risk factors for heart failure and determinants of structural and functional changes of the heart. Cardiac fibroblasts (cFB) are beyond their task as extracellular matrix-producing cells further recognized as inflammation-supporting cells. The present study aimed to evaluate the impact of sex and age on the inflammatory potential of cFB and its impact on the cardiosplenic axis and cardiac fibrosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials<\/jats:title><jats:p>Left ventricles (LV) of 3- and 12-months old male and female C57BL\/6J mice were harvested for immunohistochemistry, immunofluorescence and cFB outgrowth culture and the spleen for flow cytometry. LV-derived cFB and respective supernatants were characterized.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>LV-derived cFB from 3-months old male mice exhibited a higher inflammatory capacity, as indicated by a higher gene expression of CC-chemokine ligand (CCL) 2, and CCL7 compared to cFB derived from 3-months old female mice. The resulting higher CCL2\/chemokine C-X3-C motif ligand (Cx3CL1) and CCL7\/Cx3CL1 protein ratio in cell culture supernatants of 3-months old male vs. female cFB was reflected by a higher migration of Ly6C<jats:sup>high<\/jats:sup> monocytes towards supernatant from 3-months old male vs. female cFB. <jats:italic>In vivo<\/jats:italic> a lower ratio of splenic pro-inflammatory Ly6C<jats:sup>high<\/jats:sup> to anti-inflammatory Ly6C<jats:sup>low<\/jats:sup> monocytes was found in 3-months old male vs. female mice, suggesting a higher attraction of Ly6C<jats:sup>high<\/jats:sup> compared to Ly6C<jats:sup>low<\/jats:sup> monocytes towards the heart in male vs. female mice. In agreement, the percentage of pro-inflammatory CD68<jats:sup>+<\/jats:sup> CD206<jats:sup>\u2212<\/jats:sup> macrophages was higher in the LV of male vs. female mice at this age, whereas the percentage of anti-inflammatory CD68<jats:sup>+<\/jats:sup> CD206<jats:sup>+<\/jats:sup> macrophages was higher in the LV of 3-months old female mice compared to age-matched male animals. In parallel, the percentage of splenic TGF-<jats:italic>\u03b2<\/jats:italic><jats:sup>+<\/jats:sup> cells was higher in both 3- and 12-months old female vs. male mice, as further reflected by the higher pro-fibrotic potential of female vs. male splenocytes at both ages. In addition, female mice displayed a higher total LV collagen content compared to age-matched male mice, whereby collagen content of female cFB was higher compared to male cFB at the age of 12-months.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Age- and sex-dependent differences in cardiac fibrosis and inflammation are related to age- and sex-dependent variations in the inflammatory properties of cardiac fibroblasts.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fcvm.2023.1117419","type":"journal-article","created":{"date-parts":[[2023,11,20]],"date-time":"2023-11-20T05:25:26Z","timestamp":1700457926000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Sex- and age-related differences in the inflammatory properties of cardiac fibroblasts: impact on the cardiosplenic axis and cardiac 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