Origin and role of synovial macrophage heterogeneity in rheumatoid arthritis – SyMAC

Macrophages are mononuclear phagocytes that play crucial roles in development, tissue homeostasis, induction and resolution of immune-mediated inflammatory responses. The imprinting by the niche has considerable influence on macrophage identity and self-maintenance capacity. In contrast to many organs, tissue-resident macrophages from the joint are poorly studied. Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily affects joints where macrophages play a critical role by directly contributing to joint inflammation and to destruction of cartilage and bone. The multitude and abundance of macrophage-derived mediators in RA and their paracrine/autocrine effects identify macrophages as local and systemic amplifiers of the disease. In addition, macrophage number in the synovial membrane correlates with disease severity and treatment efficacy. Despite the major advances in understanding RA pathophysiology and the growing number of effective drugs, still a majority of all drugs are effective in only a limited number of patients, the response rate to first line treatment currently lies at an inadequate 60-70%, and remission is only achievable in 25% of the patients. We thus hypothesized that a better understanding of the origin and heterogeneity of synovial macrophages in health and disease will allow us i) deciphering the relative presence and contribution of bone marrow-derived and synovial-resident macrophages in disease features, as well as variable responses to therapies, and ii) identifying markers specific for deleterious versus beneficial subsets that could be targeted for therapeutic intervention.
Using cutting edge technologies, including an unbiased single-cell (sc)RNA-sequencing of macrophages isolated from healthy and arthritic synovial tissue in both mouse and human, longitudinal synovial biopsies in human and mice, parabiosis and fate-mapping experiments in macrophage-specific KO arthritic mice, confocal imaging, the SyMAC project aims to:
(a) Determine the proportion of synovial macrophages originating from waves of replenishment from bone-marrow monocytes and fetal-derived tissue macrophages through self-renewal in physiological conditions
(b) Investigate how each of these progenitor compartments contributes to the increased rate of macrophages into the synovium of arthritic joints during disease development and resolution phase
(c) Characterize the molecular heterogeneity of synovial macrophages under pathophysiological conditions in both mouse and human samples
(d) Identify specific markers, gene sets and pathways mediating effector versus regulatory functions of macrophages in synovial tissue development, homeostasis and contribution to arthritic processes (inflammation and erosion)
(e) Bring the proof-of-concept that specific joint macrophages subsets can be targeted for therapeutic intervention in arthritis
(f) Identify molecular markers specific for synovial macrophage subsets to stratify medicines in RA patients.

The SyMAC project will not only allow providing an in-depth cartography of the macrophage subsets at the (local) articular level in physiopathological conditions, but will also allow deciphering macrophage heterogeneity and identifying peculiar targets at different stages of the disease (initiation, inflammation peak versus resolution phase). We ultimately wish to bring in vivo proof-of-concept for clinical manipulation of macrophage subsets in arthritis to restore joint tissue homeostasis, and for the use of synovial tissue macrophage markers to stratify patients for optimized management of RA patients' treatment.