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

ABSTRACT: Pro-inflammatory activation of macrophages promotes various inflammatory disorders. The molecular mechanisms underlying macrophage activation, particularly in the context of nuclear translocation of pro-inflammatory 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 pro-inflammatory 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 pro-inflammatory activation of macrophages.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Primary Cell, Cell Culture

SUBMITTER: Sasha Singh

LAB HEAD: Masanori Aikawa

PROVIDER: PXD069750 | Pride | 2026-07-08

REPOSITORIES: Pride

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			Action	DRS
	03_JW_mSpleenMonocytes-TMT-4plex_QC_30min.raw	Raw
	03_KN_PBMC-M_IFNg_N119_N121_F12_1000x_30min.raw	Raw
	03_KN_PBMC-M_IFNg_N119_N121_F12_10x_30min.raw	Raw
	03_KN_PBMC-M_IFNg_N119_N121_QC_30min.raw	Raw
	03_KN_PBMC-M_IFNg_N119_N121_QCx10_30min.raw	Raw

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

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