RXRs

Macrophages are myeloid-derived cells that populate all tissues, where they contribute to tissue remodeling and protection against pathogens and injury. Macrophages are heterogeneous and derive from two main lineages. Tissue-resident macrophages (TRMs) arise mainly from embryonic precursors and reside in tissues for prolonged periods, whereas blood-derived macrophages are found mostly in injured tissues. 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 reside². 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), surfactant clearance by alveolar macrophages is facilitated by expression of peroxisome proliferator-activated receptor gamma (PPARγ) and iron recycling and erythrocyte phagocytosis by splenic red pulp macrophages depends on Spi-C expression.

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. 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). F4/80^HIMHCII^LO large peritoneal macrophages (LPMs) are the most abundant population in the steady-state peritoneal space. LPMs have a typical macrophage morphology, including abundant cytoplasmic vacuoles and a high capacity to phagocytose apoptotic cells, and contribute to the maintenance of intestinal microbial homeostasis by promoting the production of IgA by gut B1 cells. The small peritoneal macrophage (SPM) subset expresses lower F4/80 and higher MHCII levels and predominates after injury associated with infection or inflammation, playing important roles in bacterial removal and antigen presentation. LPMs arise mainly from embryonic precursors that are recruited to the peritoneum prior to birth, and are essentially maintained locally through self-renewal, although monocytes slowly and continuously contribute to the LPM pool. LPM maintenance is crucially dependent on the retinoic acid-dependent transcription factor GATA-6. In contrast, SPMs differentiate from circulating monocytes, in a process reliant on IRF4.

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