Nuclear RSK1 mediates interferon-γ-induced proinflammatory activation in human primary macrophages and humanized mice

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 Ser³⁸⁰ via JAK signaling, resulting in STAT1 phosphorylation at Ser⁷²⁷, 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.