Background/Purpose: Macrophages are found in nearly every tissue of the body where they maintain homeostasis and drive healthy immune response. However, macrophages are dysregulated with age and have been found to play a role in many age-associated diseases, such as arthritis. We hypothesized that macrophage dysregulation in aging stems from an increased contribution of infiltrating monocytes that have been reprogrammed by the aging environment of the bone marrow in a manner that prevents them from fully recapitulating the tissue-resident macrophage phenotype. To test this hypothesis, we are investigating aging macrophages in the murine joint synovium using functional genomic approaches.

Methods: We compared synovial macrophage composition and transcriptional profiles in young vs. aged joints from male and female mice using single-cell RNA sequencing with cell-surface protein detection (CITE-seq).

Results: We identified both conserved age-related changes and those that differed between sexes. Among synovial macrophages, we observed significant (p< 0.0001) expansion of infiltrating Ly6C+ monocytes/macrophages in both males and females (8.0% vs. 2.1%, and 9.5% vs. 2.3%, respectively) and significant reductions in the proportion of CXCR1+ lining macrophages (35.6% vs. 29.8%, and 32.4% vs. 24.9%, respectively). In females, there were significantly more MHCII+ macrophages in aged mice (17.3% vs. 12.9%) and no statistical difference in osteoclast precursors (5.8% vs. 5.3%), but in males there were significantly fewer MHCII+ macrophages in aged mice (11.3% vs. 14.7%) and significantly more osteoclast precursors (7.6% vs. 4.6%). Pseudotime analysis revealed four diverging trajectories of differentiation from infiltrating Ly6C+ monocytes/macrophages to CXCR1+ lining macrophages, AQP1+ interstitial macrophages, RELM-α+ interstitial macrophages, and osteoclast precursors, respectively, with fewer early-stage interstitial cells observed in aged mice. Total inter-macrophage heterogeneity was significantly greater in aged vs. young mice in females (p< 0.0001), but not statistically different in males. Overall, age-associated gene expression changes were not highly correlated between sexes, with mean fold-change correlations ranging from r=-0.065 in MHCII+ macrophages to r=0.23 in interstitial macrophages. Significantly enriched pathways included upregulated electron transport chain signaling in interstitial macrophages in both sexes and downregulated EGFR signaling in osteoclast precursors in females.

Conclusion: We find that monocyte-derived synovial macrophages are increased in the aging joint and synovial macrophages exhibit decreased expression of homeostatic genes. Our results provide insights on how macrophage programming changes with age and the impact on tissue health. This study will inform efforts to boost immune system function in aging.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/sex-associated-changes-to-synovial-macrophages-in-the-aging-joint/