Transcriptional profiling of macrophages in rheumatic disease for precision medicine based therapies
The Perlman Lab centers on rheumatic disease, particularly the impact that macrophages play in pathogenesis of rheumatic disease.
Macrophages have emerged as key players in the development of inflammation and fibrosis in central target organs including the synovium, kidney and lung during the pathogenesis and remission of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), respectively. Macrophages also contribute to the co-morbidities associated with these diseases including atherosclerosis and obesity. We observed marked heterogeneity in the macrophage population within diseased tissues that is dependent on their origin (embryonic vs. bone marrow derived), target organ and microenvironment. Moreover, these macrophages are extremely plastic and can alter their phenotype throughout the course of disease. Based on our data we developed a central hypothesis that during the initiation and early progression phase of disease tissue resident macrophages that normally function to maintain tolerance to local antigens, are overwhelmed by recruited pro-inflammatory or pro-fibrotic monocyte derived macrophages or pro-inflammatory dendritic cells depending on the target organ and environmental milieu. As the disease progresses to the chronic phase, however, the recruited macrophages acquire characteristics reminiscent of tissue resident macrophages while retaining a pro-inflammatory and pro-fibrotic phenotype, resulting in failed resolution of inflammation and progressive tissue destruction and fibrosis. The data anticipated from our projects would be the first to demonstrate a direct linkage of macrophage ontogeny and activation to disease activity and tissue damage. In addition, our studies allow us to explore commonalities in macrophage function between diseases that could lead to broad therapeutic interventions. In our state-of-the-art murine models we use cutting-edge technologies that we developed including micro-MRI, CT and SPECT to evaluate joint inflammation, bone destruction and lung fibrosis, Luminex-based gene arrays and multiparameter flow cytometry/sorting, whole population RNA seq and single cell RNA Seq and Chip-seq. We will cross-reference these data with those we will obtain through the AMP programs, which examine macrophage heterogeneity in the synovium and kidney from patients with rheumatic disease. This will allow us to rapidly move to functional analyses of relevant pathways and testing of new therapeutic strategies in the mouse models. I believe that our data has the potential to be paradigm shifting and transformative for the field of rheumatic disease.
24 October 2017, 12:00 (Tuesday, 3rd week, Michaelmas 2017)
Kennedy Institute of Rheumatology, Headington OX3 7FY
Bernard Sunley Lecture Theatre
Dr Harris Perlman (Northwestern University, CHI, USA)
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS)
Laura Hume (Kennedy Institute of Rheumatology),
Professor Irina Udalova (Kennedy Institute of Rheumatology),
Jo Silva (NDORMS),
Wulf Forrester-Barker (University of Oxford, Nuffield Dept of Orthopaedics Rheumatology and Musculoskeletal Sciences)
Christopher Buckley (Universities of Birmingham and Oxford)
Kennedy Institute Seminars
Members of the University only
Laura Sanchez Lazo