A Pan-family Screen of Nuclear Receptors in Immunocytes Reveals Ligand-dependent Inflammasome Control

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2024 Nov 21

PMID 39571575

Authors

Yutao Wang

Yanbo Zhang

Kyungsub Kim

Jichang Han

Daniel Okin

Zhaozhao Jiang

Liang Yang

Arum Subramaniam

Terry K Means

Frank O Nestle

Katherine A Fitzgerald

Gwendalyn J Randolph

Cammie F Lesser

Jonathan C Kagan

Diane Mathis

Christophe Benoist

Affiliations

Soon will be listed here.

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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