Inflammaging, a pro-inflammatory status that characterizes aging and primarily involving macrophages, is a master driver of age-related diseases. Mineralocorticoid receptor (MR) activation in macrophages critically regulates inflammatory and fibrotic processes. However, macrophage-specific mechanisms and the role of the macrophage MR for the regulation of inflammation and fibrotic remodeling in the aging heart have not yet been elucidated. Transcriptome profiling of cardiac macrophages from male/female young (4 months-old), middle (12 months-old) and old (18 and 24 months-old) mice revealed that myeloid cell-restricted MR deficiency prevents macrophage differentiation toward a pro-inflammatory phenotype. Pathway enrichment analysis showed that several biological processes related to inflammation and cell metabolism were modulated by the MR in aged macrophages. Further, transcriptome analysis of aged cardiac fibroblasts revealed that macrophage MR deficiency reduced the activation of pathways related to inflammation and upregulation of ZBTB16, a transcription factor involved in fibrosis. Phenotypic characterization of macrophages showed a progressive replacement of the TIMD4⁺MHC-II^neg/low macrophage population by TIMD4⁺MHC-II^int/high and TIMD4^–MHC-II^int/high macrophages in the aging heart. By integrating cell sorting and transwell experiments with TIMD4⁺/TIMD4^–macrophages and fibroblasts from old MR^flox/MR^LysMCre hearts, we showed that the inflammatory crosstalk between TIMD4^– macrophages and fibroblasts may imply the macrophage MR and the release of mitochondrial superoxide anions. Macrophage MR deficiency reduced the expansion of the TIMD4^– macrophage population and the emergence of fibrotic niches in the aging heart, thereby protecting against cardiac inflammation, fibrosis, and dysfunction. This study highlights the MR as an important mediator of cardiac macrophage inflammaging and age-related fibrotic remodeling.

炎症是一种以衰老为特征的促炎症状态，主要涉及巨噬细胞，是与年龄相关的疾病的主要驱动因素。巨噬细胞中盐皮质激素受体 (MR) 的激活对炎症和纤维化过程至关重要。然而，巨噬细胞特异性机制以及巨噬细胞MR在调节衰老心脏炎症和纤维化重塑中的作用尚未阐明。对雄性/雌性年轻（4 个月大）、中型（12 个月大）和老年（18 和 24 个月大）小鼠心脏巨噬细胞的转录组分析表明，骨髓细胞限制性 MR 缺陷阻止巨噬细胞分化为亲细胞。炎症表型。通路富集分析表明，衰老巨噬细胞中的 MR 调节了与炎症和细胞代谢相关的多种生物过程。此外，对衰老心脏成纤维细胞的转录组分析表明，巨噬细胞 MR 缺陷会减少炎症相关通路的激活以及 ZBTB16（一种参与纤维化的转录因子）的上调。巨噬细胞的表型特征显示，在衰老心脏中， TIMD4 ⁺ MHC-II ^neg/low巨噬细胞群逐渐被 TIMD4 ⁺ MHC-II ^int/high和 TIMD4 ^– MHC-II ^{int/high 巨}噬细胞取代。通过将细胞分选和transwell实验与来自老MR ^flox /MR ^{LysMCre心脏的TIMD4 +} /TIMD4 ^-巨噬细胞和成纤维细胞结合起来，我们发现TIMD4 ^-巨噬细胞和成纤维细胞之间的炎症串扰可能意味着巨噬细胞MR和线粒体超氧阴离子的释放。巨噬细胞MR缺陷减少了^TIMD4巨噬细胞群的扩张以及衰老心脏中纤维化生态位的出现，从而防止心脏炎症、纤维化和功能障碍。这项研究强调了 MR 作为心脏巨噬细胞炎症和年龄相关纤维化重塑的重要介质。