美国基因泰克公司Aditya Murthy，Shannon J. Turley和Sandra Melo Carlos共同合作，近期取得重要工作进展。他们通过系统扰动筛选确定炎症巨噬细胞状态的调节因子以及TNF mRNA m6A修饰的作用。相关研究成果2024年10月23日在线发表于《自然—遗传学》杂志上。

据介绍，巨噬细胞表现出显著的功能可塑性，这是它们在组织稳态中发挥核心作用的必要条件。在慢性炎症期间，巨噬细胞获得持续的炎症“状态”，导致疾病，但对驱动其产生的调节机制的了解有限。

研究人员描述了一种系统的功能基因组学方法，该方法将原代小鼠巨噬细胞中的全基因组表型筛查与原代人类巨噬细胞中遗传扰动的转录和细胞因子分析相结合，以揭示炎症状态的调节回路。这一过程确定了与巨噬细胞功能关键特征相关的五种不同状态的调节因子。在这些调节因子中，N⁶甲基腺苷（m6A）写入器成分的缺失消除了TNF转录物的m6A修饰，从而增强了与多种炎症病理相关的mRNA稳定性和TNF产生。因此，原代小鼠和人类巨噬细胞的表型特征描述了不同炎症状态背后的调节回路，揭示了TNF mRNA稳定性的转录后调控是先天免疫中的免疫抑制机制。

附：英文原文

Title: Systematic perturbation screens identify regulators of inflammatory macrophage states and a role for TNF mRNA m6A modification

Author: Haag, Simone M., Xie, Shiqi, Eidenschenk, Celine, Fortin, Jean-Philippe, Callow, Marinella, Costa, Mike, Lun, Aaron, Cox, Chris, Wu, Sunny Z., Pradhan, Rachana N., Lock, Jaclyn, Kuhn, Julia A., Holokai, Loryn, Thai, Minh, Freund, Emily, Nissenbaum, Ariane, Keir, Mary, Bohlen, Christopher J., Martin, Scott, Geiger-Schuller, Kathryn, Hejase, Hussein A., Yaspan, Brian L., Melo Carlos, Sandra, Turley, Shannon J., Murthy, Aditya

Issue&Volume: 2024-10-23

Abstract: Macrophages exhibit remarkable functional plasticity, a requirement for their central role in tissue homeostasis. During chronic inflammation, macrophages acquire sustained inflammatory ‘states’ that contribute to disease, but there is limited understanding of the regulatory mechanisms that drive their generation. Here we describe a systematic functional genomics approach that combines genome-wide phenotypic screening in primary murine macrophages with transcriptional and cytokine profiling of genetic perturbations in primary human macrophages to uncover regulatory circuits of inflammatory states. This process identifies regulators of five distinct states associated with key features of macrophage function. Among these regulators, loss of the N6-methyladenosine (m6A) writer components abolishes m6A modification of TNF transcripts, thereby enhancing mRNA stability and TNF production associated with multiple inflammatory pathologies. Thus, phenotypic characterization of primary murine and human macrophages describes the regulatory circuits underlying distinct inflammatory states, revealing post-transcriptional control of TNF mRNA stability as an immunosuppressive mechanism in innate immunity.

DOI: 10.1038/s41588-024-01962-w

Source: https://www.nature.com/articles/s41588-024-01962-w