A Pan-Family Screen of Nuclear Receptors in Immunocytes Reveals Ligand-Dependent Inflammasome Control

Yutao Wang,Yanbo Zhang, Kyungsub Kim,Jichang Han,Daniel Okin,Zhaozhao Jiang, Liang Yang,Arun Subramaniam, Terry K. Means,Frank O. Nestle,Katherine A. Fitzgerald,Gwendalyn J. Randolph,Cammie F. Lesser,Jonathan C. Kagan,Diane Mathis,Christophe Benoist

IMMUNITY（2024）

Harvard Med Sch | Massachusetts Gen Hosp | Washington Univ | Univ Massachusetts | Sanofi

Cited 0|Views4

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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【要点】：本研究通过全家族筛选发现，核受体家族成员在免疫细胞分化及稳态维持中具有关键作用，并揭示了视黄酸受体在调控炎症小体途径中的非常规作用。

【方法】：研究者采用“彩虹-CRISPR”筛选技术，在体内对35种核受体对主要免疫细胞类型的影响进行了全面评估。

【实验】：实验中使用了Rainbow-CRISPR技术进行全家族筛选，并在小鼠模型中研究了Rxra和Rarg基因敲除对大腹膜巨噬细胞（LPMs）的影响，发现RARγ通过调控炎症小体途径影响LPM生存。实验结果揭示了RARγ激动剂和拮抗剂在调控细胞死亡方面的作用。数据集名称未在文中提及。