Nuclear RSK1 mediates interferon-γ–induced proinflammatory activation in human primary macrophages and humanized mice
- Keishi Nihira
- Yoshihiro Yanagihara
- Yuto Nakamura
- Sarvesh Chelvanambi
- Arda Halu
- Lang Ho Lee
- Alexander Mojcher
- Hideyuki Higashi
- Iwao Yamada
- Jiao Qiao
- Andrew K. Mlynarchik
- Jianguo Wang
- Julius L. Decano
- Elena Aikawa
- Vladimir Vrbanac
- Sasha A. Singh
- Masanori Aikawa
2026-08-14
Proinflammatory activation of macrophages promotes various inflammatory disorders. The molecular mechanisms underlying macrophage activation, particularly in the context of nuclear translocation of proinflammatory response mediators, remain obscure. We have used a systems approach to explore key regulators of macrophage activation using quantitative proteomics to monitor protein translocation to the nuclei of human primary macrophages elicited with interferon-γ (IFN-γ). Unbiased bioinformatics identified several candidates, including RSK1, a ribosomal protein kinase. Network analysis linked RSK1 with human gene modules for various inflammatory disorders. In vitro mechanistic experiments showed that IFN-γ stimulation promotes RSK1 phosphorylation at Ser 380 via JAK signaling, resulting in STAT1 phosphorylation at Ser 727 , in the nuclei of macrophages. In concert with these results, RSK1 silencing or deficiency hinders IFN-γ–induced secretion of proinflammatory chemokines in human primary macrophages. Furthermore, RSK1 deficiency in human leukocytes altered IFN-γ–induced responses in humanized mice. Our findings provide evidence that RSK1 is a key nuclear shuttling enzyme that mediates proinflammatory activation of macrophages.