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Principal Investigator: Harris R Perlman
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2024
Award: $664,268
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
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.
Terms: <ATAC sequencing><ATAC-seq><ATACseq><Active Follow-up><Adopted><Adoption><Arthritis><Assay for Transposase-Accessible Chromatin using sequencing><Atrophic Arthritis><Autoregulation><B220><Basal Transcription Factor><Basal transcription factor genes><Biopsy><Blood Serum><Blood monocyte><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><CD45><Cell Body><Cells><Cellular Immune Function><Chimera><Chimera organism><Clinical><Data><Development><Dichloromethylene Diphosphonate><Disease><Disorder><Drugs><Environment><Enzyme Gene><Enzymes><Exhibits><Exposure to><Expression Signature><Future><GP180><Gene Expression Profile><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genetic><Genomic approach><Genomics><Growth><Health><Heterogeneity><Homeostasis><Immune><Immunes><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Impairment><Infiltration><Inflammation><Inflammatory><Inflammatory Arthritis><Inflammatory Infiltrate><Joints><Knock-out><Knockout><Knowledge><LY5><Label><Liposomal><Liposomes><MEF-2C><MEF2C protein><Macrophage><Maintenance><Marrow monocyte><Medication><Membrana Synovialis Capsulae Articularis><Mice><Mice Mammals><Modeling><Molecular><Murine><Mus><Mφ><PTPRC><PTPRC gene><Pathogenesis><Patients><Pharmaceutical Preparations><Phenotype><Physicians><Physiological Homeostasis><Population><Production><Recurrence><Recurrent><Recurrent disease><Relapsed Disease><Residencies><Resolution><Response to stimulus physiology><Rheumatoid Arthritis><Role><Sampling><Serum><Severities><Surface><Synovial Cell><Synovial Membrane><Synovium><T200><Testing><Therapeutic><Therapeutic Intervention><Time><Tissue Growth><Tissues><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Control><Transcriptional Regulation><Visit><Work><active followup><arthritic><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><cell type><chimeras><clodronate><combinatorial><cytokine><developmental><drug/agent><epigenomics><follow up><follow-up><followed up><followup><functional genomics><gene expression pattern><gene expression signature><genomic effort><genomic profiles><genomic strategy><immune function><inflamed joint><interstitial><intervention therapy><joint damage><joint inflammation><joint injury><joint swelling><joint trauma><minimally invasive><monocyte><mouse model><murine model><myocyte enhancer factor 2C><myocyte-specific enhancer-binding-factor 2C><ontogeny><prevent><preventing><programs><recruit><resolutions><response to therapy><response to treatment><rheumatic arthritis><scRNA-seq><side effect><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><stimulus/response><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic response><therapeutically effective><therapy response><transcription factor><transcriptional profile><transcriptional signature><treatment response><treatment responsiveness><ultrasound>