Macrophage Heterogeneity in Rheumatoid Arthritis

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Project Summary 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: tissue-resident synovial lining macrophages, tissue- resident interstitial macrophages, monocyte-derived interstitial macrophages, and infiltrating macrophages. However, we currently lack specific targets to regulate macrophage function at the molecular level in the context of developing and relapsing disease. Our prior work demonstrated that macrophage plasticity arises from the combinatorial action of cell-type-specific and environmentally driven transcription factors (TFs) which poise the epigenomic landscape for future stimulus response. Accordingly, our preliminary data confirms that murine synovial macrophage subpopulations exhibit distinct transcriptional profiles associated with different TFs at steady-state, display varying functions in a mouse model of inflammatory arthritis, and can be identified among synovial cells in patients with active RA. We hypothesize that monocyte-macrophage transition is critical for promoting joint inflammation whereas the adoption of the tissue-resident phenotype is required to maintain homeostasis. To test this hypothesis, we will use a combination of genomics approaches with lineage- tracing, bone marrow chimeras, and genetic mouse models as well as clinical samples. In Aim 1, we will murine models to determine the role of monocyte-macrophage transition in promoting joint inflammation. We will compare the transition over time in the steady-state joint to the infiltration of inflammatory macrophages in the serum transfer induced arthritis (STIA) model. In Aim 2, we will determine how the maintenance of the tissue- resident phenotype contributes to joint health using an initial and second challenge model of STIA. We will assess macrophage heterogeneity in the inflamed joint, the role of specific tissue-resident subpopulations, and molecular drivers of the tissue-residency. In Aim 3, we will use single-cell approaches on synovial tissue biopsies to determine whether the composition and transcriptional profile of macrophage subpopulations are associated with response to treatment in RA patients. Together, these aims will clarify the role of different synovial macrophage subpopulations in RA. These results will be critical to the development of targeted therapeutic interventions for RA patients.