These transcription factors form heterodimers with many other members of the nuclear receptor superfamily and also function as transcriptionally active homodimers 23. There are three RXR isotypes, RXRα (NR2B1), RXRβ (NR2B2) and RXRγ (NR2B3), which all show tissue-specific expression. They act as regulators of gene expression, exerting pleiotropic transcriptional control over a wide range of genetic programmes, including cell differentiation and survival, immune response, and lipid and glucose metabolism 21, 22. Retinoid X receptors (RXRs) are members of the nuclear receptor superfamily of ligand-dependent transcription factors. In contrast, SPMs differentiate from circulating monocytes, in a process reliant on IRF4 20. LPM maintenance is crucially dependent on the retinoic acid-dependent transcription factor GATA-6 11, 18, 19. LPMs arise mainly from embryonic precursors that are recruited to the peritoneum prior to birth, and are essentially maintained locally through self-renewal 13, 14, although monocytes slowly and continuously contribute to the LPM pool 15, 16, 17. The small peritoneal macrophage (SPM) subset expresses lower F4/80 and higher MHCII levels and predominates after injury associated with infection or inflammation 9, playing important roles in bacterial removal and antigen presentation 8, 9, 12. LPMs have a typical macrophage morphology, including abundant cytoplasmic vacuoles and a high capacity to phagocytose apoptotic cells 9, 10, and contribute to the maintenance of intestinal microbial homeostasis by promoting the production of IgA by gut B1 cells 11. F4/80 HIMHCII LO large peritoneal macrophages (LPMs) are the most abundant population in the steady-state peritoneal space. In mice, the peritoneal and pleural cavities contain two macrophage subsets distinguished phenotypically by their size and differential expression of F4/80 and MHC class II (MHCII) 9. The peritoneal and pleural cavities are small fluid-filled spaces that contain a large population of immune cells, including T and B cells, mastocytes, dendritic cells, monocytes and macrophages 8. For example, the ability of splenic marginal zone macrophages to trap circulating particulates and engulf marginal zone B cells is controlled by liver X receptor alpha (LXRα) 5, surfactant clearance by alveolar macrophages is facilitated by expression of peroxisome proliferator-activated receptor gamma (PPARγ) 6 and iron recycling and erythrocyte phagocytosis by splenic red pulp macrophages depends on Spi-C expression 7. In a previous analysis by RNA-seq, ChIP-seq and assay for transposase-accessible chromatin with sequencing (ATAC-seq) of purified TRMs from six organs, we showed that the TRM epigenetic and transcriptional programme is unique to each tissue and is shaped by the tissue microenvironment in which TRMs reside 2, 4. Tissue-resident macrophages (TRMs) arise mainly from embryonic precursors 2 and reside in tissues for prolonged periods, whereas blood-derived macrophages are found mostly in injured tissues 3. Macrophages are heterogeneous and derive from two main lineages. Macrophages are myeloid-derived cells that populate all tissues, where they contribute to tissue remodelling and protection against pathogens and injury 1. Our study reveals that RXR signalling controls the maintenance of the serous macrophage pool and that targeting peritoneal LPMs may improve ovarian cancer outcomes. We also find that peritoneal LPMs infiltrate early ovarian tumours and that RXR deletion diminishes LPM accumulation in tumours and strongly reduces ovarian tumour progression in mice. RXR deficiency impairs neonatal expansion of the LPM pool and reduces the survival of adult LPMs through excess lipid accumulation. Here, we show that RXRs control mouse serous-macrophage identity by regulating chromatin accessibility and the transcriptional regulation of canonical macrophage genes. We recently found that serous-cavity TRMs (LPMs) are highly enriched in RXR transcripts and RXR-response elements. However, TRM identity and the mechanisms that maintain TRMs in tissues remain poorly understood.
TRMs express a molecular program that is mostly shaped by tissue cues. Tissue-resident macrophages (TRMs) populate all tissues and play key roles in homeostasis, immunity and repair.