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Neuropsychiatric SLE (NPSLE) occurs in 30\u201340% of lupus patients and is the most severe presentation of SLE, frequently resulting in limitation of daily life. Recent studies have shown that microglia, tissue\u2010resident macrophages in the central nervous system, are involved in the pathogenesis of NPSLE. This study was undertaken to explore new therapeutic targets for NPSLE focusing on microglia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>RNA sequencing of microglia in MRL\/<jats:italic>lpr<\/jats:italic>, lupus\u2010prone mice, as well as that of microglia cultured in vitro with cytokines were performed. A candidate gene, which could be a therapeutic target for NPSLE, was identified, and its role in microglial activation and phagocytosis was investigated using specific inhibitors and small interfering RNA. The effect of intracerebroventricular administration of the inhibitor on the behavioral abnormalities of MRL\/<jats:italic>lpr<\/jats:italic> was also evaluated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Transcriptome analysis revealed the up\u2010regulation of <jats:italic>Ikbke<\/jats:italic>, which encodes the inhibitor of NF\u2010\u03baB kinase subunit \u025b (IKBK\u03b5) in both microglia from MRL\/<jats:italic>lpr<\/jats:italic> mice and cytokine\u2010stimulated microglia in vitro. Intracerebroventricular administration of an IKBK\u03b5 inhibitor ameliorated cognitive function and suppressed microglial activation in MRL\/<jats:italic>lpr<\/jats:italic> mice. Mechanistically, IKBK\u03b5 inhibition reduced glycolysis, which dampened microglial activation and phagocytosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings suggest that IKBK\u03b5 plays a vital role in the pathogenesis of NPSLE via microglial activation, and it could serve as a therapeutic target for NPSLE.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42352","type":"journal-article","created":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T09:01:53Z","timestamp":1663059713000},"page":"411-423","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Inhibitor of <scp>NF\u2010\u03baB<\/scp> Kinase Subunit \u03b5 Contributes to Neuropsychiatric Manifestations in <scp>Lupus\u2010Prone<\/scp> Mice Through Microglial Activation"],"prefix":"10.1002","volume":"75","author":[{"given":"Kohei","family":"Karino","sequence":"first","affiliation":[{"name":"Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine Hokkaido University  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7663-534X","authenticated-orcid":false,"given":"Michihito","family":"Kono","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine Hokkaido University  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuhei","family":"Takeyama","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine Hokkaido University  Sapporo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Kudo","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School 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