Extended Data Fig. 10: Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis.

The HEALTHY synovial membrane (SM) contains predominantly MerTK^pos STMs with two subpopulations: TREM2^pos and LYVE1^pos. Their transcriptomics suggest immunoregulatory functions, for example production of retinoic acid. In ACTIVE RA, the synovial membrane is infiltrated by MerTK^negCD48^pos STMs with two main phenotypes, expressing either S100A alarmins and IL-1β, or osteopontin (SPP1); both are the main source of pathogenic TNF and IL-6, and potent contact-dependent inducers of chemokines and MMPs from synovial fibroblasts (FLS). RA in REMISSION is characterized by restoration of MerTK^posTREM2^pos and MerTK^posLYVE1^pos subpopulations. Their transcriptome is characterized by MerTK-dependent transcription factors that are negative-regulators of inflammation. They are low producers of pro-inflammatory cytokines; further downregulated by locally-produced GAS6. Instead they produce resolvins and induce a repair response in FLS. Their relative proportion in remission was indicative of flare after treatment cessation. When the proportion of MerTK^pos STMs becomes less than 47.5%, (or the ratio of MerTK^pos to MerTK^neg becomes less than 2.5) there is a likelihood of FLARE after treatment cessation. MerTK^neg STMs in patients predicted to flare have a CD48^posS100A12^pos phenotype that releases the alarmin S100A12 upon stimulation, suggesting a role in the initiation of flare. BM bone marrow; MMPs, matrix metalloproteinases; KLFs krueppel like factors; NR4As, nuclear receptor subfamily 4 group A; ATF3, cAMP-dependent transcription factor 3; TREM2, triggering receptor expressed on myeloid cells 2; LYVE1, lymphatic vessels endothelial hyaluronan receptor 1; FOLR2, folate receptor beta; GAS6, growth arrest-specific 6; S100A12, S100 calcium-binding protein A12; THY1, CD90.