Macrophage mineralocorticoid receptor drives inflammaging in adipose tissue

Background/Introduction Age-associated adipose tissue inflammation, largely driven by macrophages, is increasingly recognized as a key contributor to metabolic dysregulation and cardiovascular disease/aging. Mineralocorticoid receptor (MR) activation promotes cardiac macrophage inflammaging and aggravates coronary and cardiac dysfunction associated with excess visceral adiposity. Purpose We aimed to determine the role of macrophage MR signaling in regulating age-related adipocyte/adipose tissue inflammation and remodeling. Methods We performed transcriptome profiling of visceral adipose tissue macrophages (VATMs) from male/female MRflox and MRLysMCre mice across aging. Moreover, VATM heterogeneity was investigated via multiparametric flow cytometry and multicolor immunofluorescence. Adipocyte remodeling and adipose tissue alterations (crown-like structures, cell senescence, fibrosis and neurovascular networks) were examined over the course of aging. In addition, we conducted an analysis of published single-nucleus RNA-sequencing data from aging human abdominal white adipose tissue. Results Transcriptome analysis of VATMs, identified as LIN- (Ter119, CD19, SiglecF, CD3, Ly6C, Ly6G)/CD11b+/F4/80+/CD64+/CD63+/CD9+, revealed that multiple genes and signaling pathways involved in inflammation and adipose tissue remodeling are regulated by the MR during aging. Moreover, phenotypic characterization showed a progressive increase in the CD11c+/CD9+/CD226- macrophage subpopulation (CD226-LAM) in aging visceral adipose tissue. Single-cell transcriptomic re-analysis demonstrated that aging human adipose tissue is associated with a significantly expanded CD226-LAM subpopulation, which exhibits age-dependent upregulation of MR expression. Mechanistically, macrophage-specific MR deficiency prevented the expansion of the CD226-LAM population and the activation of genes and pathways related to inflammaging in CD226-LAMs. Moreover, macrophage MR deficiency reduced inflammatory activation of visceral adipocytes and improved adipose tissue remodeling, including crown-like structure formation, cellular senescence and fibrosis, across aging. Conclusion Our findings identify macrophage MR signaling as a critical regulator of adipose tissue inflammaging/remodeling and suggest it as a potential target to mitigate cardiometabolic dysfunction.