Elp3; mTORC2; macrophage polarization; mitochondrial translation; tRNA modifications; Neuroscience (all); Molecular Biology; Biochemistry, Genetics and Molecular Biology (all); Immunology and Microbiology (all); General Immunology and Microbiology; General Biochemistry, Genetics and Molecular Biology; General Neuroscience
[en] Macrophage polarization is a process whereby macrophages acquire distinct effector states (M1 or M2) to carry out multiple and sometimes opposite functions. We show here that translational reprogramming occurs during macrophage polarization and that this relies on the Elongator complex subunit Elp3, an enzyme that modifies the wobble uridine base U34 in cytosolic tRNAs. Elp3 expression is downregulated by classical M1-activating signals in myeloid cells, where it limits the production of pro-inflammatory cytokines via FoxO1 phosphorylation, and attenuates experimental colitis in mice. In contrast, alternative M2-activating signals upregulate Elp3 expression through a PI3K- and STAT6-dependent signaling pathway. The metabolic reprogramming linked to M2 macrophage polarization relies on Elp3 and the translation of multiple candidates, including the mitochondrial ribosome large subunit proteins Mrpl3, Mrpl13, and Mrpl47. By promoting translation of its activator Ric8b in a codon-dependent manner, Elp3 also regulates mTORC2 activation. Elp3 expression in myeloid cells further promotes Wnt-driven tumor initiation in the intestine by maintaining a pool of tumor-associated macrophages exhibiting M2 features. Collectively, our data establish a functional link between tRNA modifications, mTORC2 activation, and macrophage polarization.
Funding text :
The authors are grateful to the GIGA Imaging platform for the FACS analyses. They also thank Dr. Zhang from NIBIO (Olso, Norway) for providing us R scripts on RNA‐seq and proteomics analysis. This work was supported by grants from WELBIO (WELBIO‐CR‐2019C‐02R), FNRS/TELEVIE, the Belgian Foundation against Cancer (FBC/2020/1323), the University of Liege (ARC UBICOREAR) and by the Leon Fredericq Foundation (Faculty of Medicine, CHU of Liege). PC and AC are Senior Research Associate and Research Director at the FNRS, respectively.