美国哈佛医学院Christophe Benoist小组发现，核受体泛家族筛选揭示配体依赖的免疫细胞炎性小体调控。2024年11月20日，《免疫》杂志在线发表了这项成果。

研究人员通过“Rainbow-CRISPR”筛选法，揭示了35种核受体（NR）对体内所有主要免疫细胞类型的分化和稳态维持的影响。视黄酸受体在细胞特异性作用中占据了最频繁的角色。不同组织的常驻巨噬细胞对NR的需求有所不同。删除Rxra或Rarg基因会减少GATA6⁺大腹膜巨噬细胞（LPM）的频率。

视黄醇X受体α（RXRα）通过表观遗传和转录调控常规地协调LPM分化，而视黄酸受体γ（RARγ）则通过与炎性小体适配蛋白ASC的结合调控LPM的生存和程序性焦亡。RARγ拮抗剂激活了半胱天冬酶，而RARγ激动剂则抑制了多种炎性小体激活剂引起的细胞死亡。

该研究为NR在免疫系统中的功能提供了广泛的视角，并揭示了视黄酸受体在调节炎性小体通路中的非经典作用。

研究人员表示，NR家族的配体依赖型转录因子调控着后生动物生物学的各个方面，能够通过小的亲脂分子促进远距离器官之间的通讯。

附：英文原文

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

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

Issue&Volume: 2024-11-20

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.

DOI: 10.1016/j.immuni.2024.10.010

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00490-4