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

• Published in: Nature genetics Vol. 56; no. 11; pp. 2493 - 2505
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 23-10-2024
• Subjects: 13/21; 631/1647/2163; 631/250; Agriculture; Animal Genetics and Genomics; Biomedical and Life Sciences; Biomedicine; Cancer Research; Gene Function; Human Genetics
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-024-01962-w

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
N
6
-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.
Functional screens using mouse and human primary macrophages identify regulators of distinct inflammatory states, including a role for m6A mRNA modification in TNF production.