Macrophage Heterogeneity in Rheumatoid Arthritis

Project: Research project

Project Details


Macrophages are critical to the pathogenesis of rheumatoid arthritis (RA), but several distinct macrophage subpopulations co-exist in the synovium of joints. In steady-state, tissue-resident macrophages contribute to joint integrity and are required for tissue homeostasis. While increased numbers of macrophages during the development of arthritis is associated with inflammation and joint damage, depletion of all macrophages delays resolution in a mouse model of arthritis. Thus, broad targeting of macrophages is unlikely to provide an effective therapeutic option for rheumatoid arthritis. Instead, we propose to characterize the function of synovial macrophage subpopulations in healthy and inflamed joint to determine how they contribute to the pathogenesis of arthritis. We and others have identified at least 4 synovial macrophage subpopulations that differ in their ontogeny and localization within the joint: synovial lining macrophages, tissue-resident interstitial macrophages, monocyte-derived interstitial macrophages, and infiltrating macrophages. Our prior work demonstrated that such macrophage plasticity arises from the combinatorial action of cell-type-specific and environmentally driven transcription factors (TFs). Accordingly, our preliminary data confirms that synovial macrophage subpopulations exhibit distinct gene expression profiles associated with different TFs. By altering the activity of key genes and TFs in macrophages, we test the role of these subpopulations. We hypothesize that the synovial lining macrophage subpopulation is required to maintain and restore joint health while infiltrating macrophages contribute to inflammation. To test this hypothesis, we will use a combination of genomics approaches with lineage-tracing, bone marrow chimera, and cell-type-specific genetic knockouts. In Aim 1, we will murine models to determine how the depletion of different macrophage subpopulations in steady-state impacts joint health. In Aim 2, we will determine which subpopulations contribute to the initiation, progression, resolution, and flare of inflammation in a mouse model of arthritis. In Aim 3, we will determine whether macrophage heterogeneity in the joint can predict the occurrence of flares in RA patients through single-cell analysis of synovial biopsy tissues. Together, these aims will clarify the role of different macrophage subpopulations in RA. These results will be crucial to developing targeted therapeutic interventions for RA patients.
Effective start/end date4/15/222/28/27


  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (5R01AR080513-02)


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