Treatment-refractory rheumatoid arthritis (RA) is a major clinical challenge. Drug-free remission is uncommon but provides proof-of-concept that articular immune-homeostasis can be reinstated. Here we identify active cellular and molecular mechanisms of sustained remission in RA. Single-cell transcriptomics (32,000 cells) identified phenotypic changes in synovial tissue macrophages (STM) spanning health, early/active RA, treatment-refractory/active RA, and RA in sustained remission. Each clinical state is characterised by different frequencies of 9 discrete phenotypes of 4 distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas combined with deep-phenotypic, spatial and functional analyses of synovial biopsy FACSsorted STMs revealed two STM subpopulations (MerTK/TREM2 high and MerTK/FOLR2/LYVE1 pos ) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. In response to damage signals these cells are potent producers of inflammation-resolving lipid mediators and are the only STMs that induce the repair response of synovial fibroblasts. A low proportion of MerTK pos STMs in remission RA is a prognostic biomarker predictive of flare after treatment cessation. Therapeutic enhancement of MerTK pos STM-subsets could encourage resolution of inflammation and reinstate synovial homeostasis in inflammatory arthritis.

A combination of cis-regulatory elements can impose the formation of an early replicating domain in a naturally late replicating region and might constitute the basic unit of early replicating domains.

Eukaryotic genomes are replicated under the control of a highly sophisticated program during the restricted time period corresponding to S phase. The most widely used replication timing assays, which are performed on populations of millions of cells, suggest that most of the genome is synchronously replicated on homologous chromosomes. We investigated the stochastic nature of this temporal program, by comparing the precise replication times of allelic loci within single vertebrate cells progressing through S phase at six loci replicated from very early to very late. We show that replication timing is strictly controlled for the three loci replicated in the first half of S phase. Out of the three loci replicated in the second part of S phase, two present a significantly more stochastic pattern. Surprisingly, we find that the locus replicated at the very end of S phase, presents stochasticity similar to those replicated in early S phase. We suggest that the richness of loci in efficient origins of replication, which decreases from early- to late-replicating regions, and the strength of interaction with the nuclear lamina may underlie the variation of timing control during S phase.