Spatiotemporal molecular profiling of macrophage-fibroblast crosstalk defines checkpoints orchestrating onset and resolution of inflammation

The molecular details of macrophage-fibroblast crosstalk during the onset and resolution of inflammatory disease remain incompletely understood. Here, we apply a bioinformatic modeling approach based on single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin using sequencing to map heterocellular signaling circuits of synovial macrophage and synovial fibroblast (SF) subsets during various stages of inflammatory arthritis. While SFs function as key pacemakers of synovial inflammation, individual subsets of synovial macrophages support both the perpetuation and the resolution of arthritis. Pro-inflammatory Il1b⁺ macrophages dominate the early stages of inflammation and retain a substantial intrinsic plasticity that is characterized by chromatin remodeling and an eventual differentiation into Spp1⁺ macrophages. These cells display a terminally differentiated phenotype, suppress the activation of pro-inflammatory SFs, and initiate the resolution of arthritis by secretion of regulatory mediators, including osteopontin. Our data highlight the dichotomous character of macrophage-fibroblast crosstalk and define the cellular and molecular checkpoints that control the onset and resolution of immune-mediated inflammatory diseases.