AUTHOR=Pappritz Kathleen , Puhl Sarah-Lena , Matz Isabel , Brauer Erik , Shia Yi Xuan , El-Shafeey Muhammad , Koch Suzanne E. , Miteva Kapka , Mucha Christin , Duda Georg N. , Petersen Ansgar , Steffens Sabine , Tschöpe Carsten , Van Linthout Sophie 

TITLE=Sex- and age-related differences in the inflammatory properties of cardiac fibroblasts: impact on the cardiosplenic axis and cardiac fibrosis

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=Volume 10 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2023.1117419

DOI=10.3389/fcvm.2023.1117419

ISSN=2297-055X

ABSTRACT=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.
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.
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 versus female cFB was reflected by a higher migration of Ly6Chigh monocytes towards supernatant from 3-months old male versus female cFB. In vivo a lower ratio of splenic pro-inflammatory Ly6Chigh to anti-inflammatory Ly6Clow monocytes was found in 3-months old male versus female mice, suggesting a higher attraction of Ly6Chigh compared to Ly6Clow monocytes towards the heart in male versus female mice. In agreement, the percentage of pro-inflammatory CD68+CD206-macrophages was higher in the LV of male versus female mice at this age, whereas the percentage of antiinflammatory CD68+CD206+ 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-b+ cells was higher in both 3-and 12-months old female versus male mice, as further reflected by the higher profibrotic potential of female versus 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.
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.