A pan-family screen of nuclear receptors in immunocytes reveals ligand-dependent inflammasome control

Immunity. 2024 Dec 10;57(12):2737-2754.e12. doi: 10.1016/j.immuni.2024.10.010. Epub 2024 Nov 20.

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.

MeSH terms

  • Animals
  • CARD Signaling Adaptor Proteins / metabolism
  • CRISPR-Cas Systems
  • Cell Differentiation
  • GATA6 Transcription Factor / metabolism
  • Inflammasomes* / immunology
  • Inflammasomes* / metabolism
  • Ligands
  • Macrophages, Peritoneal / immunology
  • Macrophages, Peritoneal / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pyroptosis / immunology
  • Receptors, Cytoplasmic and Nuclear* / metabolism
  • Receptors, Retinoic Acid / metabolism
  • Retinoic Acid Receptor gamma
  • Retinoid X Receptor alpha / metabolism

Substances

  • Inflammasomes
  • Receptors, Cytoplasmic and Nuclear
  • Ligands
  • Retinoic Acid Receptor gamma
  • Receptors, Retinoic Acid
  • CARD Signaling Adaptor Proteins
  • GATA6 Transcription Factor
  • Retinoid X Receptor alpha