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It is characterized by progressive stenosis or occlusion of terminal internal carotid arteries. Although inflammatory and autoimmune responses have been implicated in MMD pathogenesis, the precise molecular mechanisms underlying the disease remain poorly understood. RNF213, a key susceptibility gene for MMD, has been linked to inflammatory signaling; however, its role in NF-\u03baB-driven inflammation remains unclear. Here, we identify RNF213 as a critical regulator of the IL-6 amplifier (IL6-Amp), a mechanism that enhances NF-\u03baB-mediated inflammation in the presence of IL-6-STAT3 in non-immune cells. RNF213 knockdown reduced IL-6 expression in H4 cells, a model for IL6-Amp induction via tumor necrosis factor (TNF)-\u03b1 and IL-6 co-stimulation, selectively suppressing NF-\u03baB target genes. In vivo, RNF213 depletion attenuated inflammation in an NF-\u03baB-dependent imiquimod-induced ear swelling model. The MMD-associated RNF213 p.R4810K variant enhanced NF-\u03baB activation by strengthening the interaction between RNF213 and TRAF2, a key adaptor in TNF-\u03b1\u2013NF-\u03baB signaling. Consistent with these findings, histopathological analysis of superficial temporal arteries from MMD patients revealed genotype-dependent IL6-Amp activation, with pronounced phosphorylation of NF-\u03baB p65 and STAT3 in homozygous carriers. In contrast, heterozygous and wild-type vessels showed minimal basal activation, but in vitro stimulation of arachnoid cells from a heterozygous patient recapitulated IL6-Amp responsiveness. Collectively, these findings establish RNF213 as a pivotal regulator of NF-\u03baB-driven inflammation and suggest that the p.R4810K variant amplifies inflammatory signaling, thereby contributing to MMD pathogenesis. This study not only advances our understanding of MMD pathophysiology but also highlights potential therapeutic strategies targeting inflammation.<\/jats:p>","DOI":"10.1093\/intimm\/dxag011","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T12:47:36Z","timestamp":1773924456000},"page":"494-505","source":"Crossref","is-referenced-by-count":4,"title":["RNF213\u2013TRAF2 interaction enhances inflammatory responses via NF-\u03baB activation in moyamoya disease"],"prefix":"10.1093","volume":"38","author":[{"given":"Mitsutaka","family":"Yasuda","sequence":"first","affiliation":[{"name":"Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University , Sapporo 060-0815 ,","place":["Japan"]},{"name":"Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University , Sapporo 060-0815 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,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Quantum Immunology Team, Institute for Quantum Life Science, National Institute for Quantum and Radiological Science and Technology (QST) , Chiba 263-8555 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University , Sapporo 060-0815 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rie","family":"Hasebe","sequence":"additional","affiliation":[{"name":"Division of Molecular Neuroimmunology, Department of Homeostatic Regulation, National Institute for Physiological Sciences, National Institutes of Natural Sciences , Aichi 444-8585 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,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shintaro","family":"Hojyo","sequence":"additional","affiliation":[{"name":"Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University , Sapporo 060-0815 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Atsumi","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University , Sapporo 060-0815 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University , Sapporo 060-0815 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