AI Article Synopsis

  • The study investigates how 35 nuclear receptors (NRs) influence the differentiation and maintenance of key immune cells using a method called "Rainbow-CRISPR."
  • It finds that receptors for retinoic acid have significant and specific roles in various immune cell types, particularly in macrophages.
  • Notably, it uncovers a unique function of the retinoic acid receptor gamma (RARγ) in regulating immune cell survival and inflammasome activity, revealing its dual role in promoting health or cell death in macrophages.

Article Abstract

Ligand-dependent transcription factors of the nuclear receptor (NR) family regulate diverse aspects of metazoan biology, enabling communications between distant organs via small lipophilic molecules. Here, we examined the impact of each of 35 NRs on differentiation and homeostatic maintenance of all major immunological cell types in vivo through a "Rainbow-CRISPR" screen. Receptors for retinoic acid exerted the most frequent cell-specific roles. NR requirements varied for resident macrophages of different tissues. Deletion of either Rxra or Rarg reduced frequencies of GATA6 large peritoneal macrophages (LPMs). Retinoid X receptor alpha (RXRα) functioned conventionally by orchestrating LPM differentiation through chromatin and transcriptional regulation, whereas retinoic acid receptor gamma (RARγ) controlled LPM survival by regulating pyroptosis via association with the inflammasome adaptor ASC. RARγ antagonists activated caspases, and RARγ agonists inhibited cell death induced by several inflammasome activators. Our findings provide a broad view of NR function in the immune system and reveal a noncanonical role for a retinoid receptor in modulating inflammasome pathways.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11634661PMC
http://dx.doi.org/10.1016/j.immuni.2024.10.010DOI Listing

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