ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
This article is part of the Research TopicCharacterizing the Functional Heterogeneity of Synovial MacrophagesView all 5 articles
Sex-associated transcriptional changes to synovial macrophages in the aging joint
Provisionally accepted
Matthew Dapas1
Erica de Jong2Yidan Wang1Cally Mills1
Samuel D. Dowling1Tyler Austin Therron1Samuel Dadd Hamilton1
Carla Marie Cuda1
Dawn M.E. Bowdish2
Deborah R. Winter1*- 1Northwestern University, Evanston, United States
- 2McMaster University Immunology Research Centre, Hamilton, Canada
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Background: Synovial macrophages are critical to tissue maintenance and immune homeostasis in the joints. However, the function of synovial macrophages is compromised with age, leading to increased susceptibility to chronic inflammation and arthritis. Here, we compare the transcriptional heterogeneity of synovial macrophages in young and old joints from male and female mice to better understand the impact of aging and the role of sex. Methods: We compared synovial macrophage composition and transcriptional profiles in young vs. old joints from male and female mice using single-cell RNA sequencing with cell-surface protein detection (CITE-seq). Results: We defined five major synovial macrophage subpopulations: CX3CR1+ lining, CD163+ interstitial, MHCII+ monocyte-derived, Ly6C+ infiltrating, and Ctsk-expressing osteoclast-like cells, across age and sex. Ly6C+ macrophages were expanded in old mice of both sexes compared to young, while CX3CR1+ lining macrophages were reduced. MHCII+ macrophage proportion differed between sexes, with Arg1-expressing cells driving an increase in females and a decrease in males with age. Age-associated differential expression was positively correlated between sexes with the exception of the MHCII+ subpopulations. Significantly enriched pathways included upregulated electron transport chain signaling in interstitial macrophages in both sexes and significantly downregulated MAPK signaling in Ctsk+ macrophages in females. Trajectory analysis suggested that the aging synovial macrophage compartment was depleted for transitional cells, which may indicate a macrophage differentiation defect. Conclusions: In summary, we report on both conserved age-related changes and those that differed between males and females. Our results provide insights on how macrophage heterogeneity changes with age in a sex-dimorphic manner and lays the foundation for research into their role in age-associated diseases, such as arthritis.
Keywords: Aging, CITE-seq, Joints, macrophage, Synovial macrophages
Received: 13 Oct 2025; Accepted: 22 Jan 2026.
Copyright: © 2026 Dapas, de Jong, Wang, Mills, Dowling, Therron, Hamilton, Cuda, Bowdish and Winter. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Deborah R. Winter
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