2. Academic Validation
  3. A pan-family screen of nuclear receptors in immunocytes reveals ligand-dependent inflammasome control

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.
Yutao Wang 1,  Yanbo Zhang 1,  Kyungsub Kim 2,  Jichang Han 3,  Daniel Okin 4,  Zhaozhao Jiang 5,  Liang Yang 1,  Arum Subramaniam 6,  Terry K Means 6,  Frank O Nestlé 6,  Katherine A Fitzgerald 5,  Gwendalyn J Randolph 3,  Cammie F Lesser 2,  Jonathan C Kagan 4,  Diane Mathis 1,  Christophe Benoist 7
Affiliations

Affiliations

  • 1 Department of Immunology, Harvard Medical School, Boston, MA, USA.
  • 2 Center for Bacterial Pathogenesis and Department of Microbiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • 3 Department of Pathology, Washington University School of Medicine, St. Louis, MO, USA.
  • 4 Division of Gastroenterology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
  • 5 Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
  • 6 Immunology and Inflammatory Research Therapeutic Area, Sanofi, Cambridge, MA, USA.
  • 7 Department of Immunology, Harvard Medical School, Boston, MA, USA. Electronic address: cbdm@hms.harvard.edu.
PMID: 39571575 DOI: 10.1016/j.immuni.2024.10.010
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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