RXRs control serous macrophage neonatal expansion and identity and contribute to ovarian cancer progression

• Published in: Nature communications Vol. 11; no. 1; p. 1655
• Main Authors: Casanova-Acebes, María, Menéndez-Gutiérrez, María Piedad, Porcuna, Jesús, Álvarez-Errico, Damiana, Lavin, Yonit, García, Ana, Kobayashi, Soma, Le Berichel, Jessica, Núñez, Vanessa, Were, Felipe, Jiménez-Carretero, Daniel, Sánchez-Cabo, Fátima, Merad, Miriam, Ricote, Mercedes
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03-04-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/2; 13/31; 13/51; 14/1; 14/19; 14/34; 14/63; 38/39; 38/77; 38/91; 631/250/2504/342/1956; 631/337/2019; 631/67/1517/1709; 631/80/86/2363; 64/60; Accumulation; Animals; Animals, Newborn - immunology; Cancer; Chromatin; Disease Progression; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation; Gene regulation; Homeostasis; Humanities and Social Sciences; Lipid metabolism; Lipids; Macrophages; Macrophages, Peritoneal - metabolism; Mice; Mice, Inbred C57BL; multidisciplinary; Neonates; Ovarian cancer; Ovarian Neoplasms - immunology; Peritoneum; Regulatory sequences; Retinoid X receptors; Retinoid X Receptors - metabolism; Science; Science (multidisciplinary); Signal Transduction; Signaling; Survival; Tissues; Transcription; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15371-0

Tissue-resident macrophages (TRMs) populate all tissues and play key roles in homeostasis, immunity and repair. TRMs express a molecular program that is mostly shaped by tissue cues. However, TRM identity and the mechanisms that maintain TRMs in tissues remain poorly understood. We recently found that serous-cavity TRMs (LPMs) are highly enriched in RXR transcripts and RXR-response elements. Here, we show that RXRs control mouse serous-macrophage identity by regulating chromatin accessibility and the transcriptional regulation of canonical macrophage genes. RXR deficiency impairs neonatal expansion of the LPM pool and reduces the survival of adult LPMs through excess lipid accumulation. 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. Our study reveals that RXR signalling controls the maintenance of the serous macrophage pool and that targeting peritoneal LPMs may improve ovarian cancer outcomes.
Macrophages can differentiate to perform homeostatic tissue-specific functions. Here the authors show that RXR signalling is critical for large peritoneal macrophage (LPM) expansion during neonatal life and LPM lipid metabolism and survival during adult homeostasis, and that ovarian cancer growth relies on RXR-dependent LPMs.