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Adv."],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:p>\n                    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-\u03b3 (IFN-\u03b3). 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-\u03b3 stimulation promotes RSK1 phosphorylation at Ser\n                    <jats:sup>380<\/jats:sup>\n                    via JAK signaling, resulting in STAT1 phosphorylation at Ser\n                    <jats:sup>727<\/jats:sup>\n                    , in the nuclei of macrophages. In concert with these results, RSK1 silencing or deficiency hinders IFN-\u03b3\u2013induced secretion of proinflammatory chemokines in human primary macrophages. Furthermore, RSK1 deficiency in human leukocytes altered IFN-\u03b3\u2013induced responses in humanized mice. Our findings provide evidence that RSK1 is a key nuclear shuttling enzyme that mediates proinflammatory activation of macrophages.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.ady4193","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T17:58:41Z","timestamp":1786730321000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Nuclear RSK1 mediates interferon-\u03b3\u2013induced proinflammatory activation in human primary macrophages and humanized mice"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3797-9289","authenticated-orcid":true,"given":"Keishi","family":"Nihira","sequence":"first","affiliation":[{"name":"Center for Interdisciplinary Cardiovascular Sciences, Cardiovascular Division, Department of Medicine, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115, 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