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Y-box binding protein 1 (YB-1) regulates pro-inflammatory gene expression intracellularly and can be secreted to function extracellularly, yet how these two compartments jointly influence early IRI pathology remains poorly understood. To dissect the roles of intracellular myeloid versus extracellular YB-1, we subjected myeloid-specific Ybx1 knockout, Ybx1fl\/fl \u00d7 LysMcre, mice and wild-type (WT) littermates to unilateral renal IRI following administration of either a neutralizing anti-YB-1 antibody or control IgG. Kidney injury, inflammation, immune cell recruitment, neutrophil extracellular trap (NET) formation, antibody localization, and Fc\u03b3 receptor expression were assessed by qRT-PCR, histology, immunostaining, Western blotting, and flow cytometry. Myeloid-specific knockout of Ybx1 markedly reduced renal inflammation, neutrophil infiltration, NET formation, and tubular injury. This protective phenotype was lost when extracellular YB-1 was simultaneously reduced: anti-YB-1 treatment in knockout mice restored pro-inflammatory cytokine expression, increased tubular damage markers such as NGAL and KIM-1, exacerbated neutrophil recruitment and NET formation, and led to luminar accumulation of YB-1\/anti-YB-1 immune complexes in tubular cells. Mechanistically, Ybx1-deficient myeloid cells exhibited significantly reduced CD16 expression, pointing to impaired Fc\u03b3 receptor-mediated phagocytosis as the cause of defective immune complex clearance. In contrast, wild-type mice efficiently cleared extracellular YB-1 complexes and showed no injury aggravation upon antibody treatment. Our findings identify myeloid YB-1 as a central regulator of early inflammatory injury in renal IRI and reveal that its protective depletion becomes pathogenic when extracellular YB-1 is simultaneously neutralized, likely due to unmasked defects in immune complex clearance.<\/jats:p>","DOI":"10.3390\/ijms27125239","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T06:33:44Z","timestamp":1781073224000},"page":"5239","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["When Protection Turns Pathogenic: Dual Compartment Functions of Myeloid YB-1 in Renal IRI"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0993-1595","authenticated-orcid":false,"given":"Anna","family":"Leitz","sequence":"first","affiliation":[{"name":"Department of Nephrology and Clinical Immunology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany"},{"name":"Faculty of Medicine, Institute of Immunology, RWTH Aachen University Hospital, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yili","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Clinical Immunology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiyang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Clinical Immunology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingying","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Clinical Immunology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Clinical Immunology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany"},{"name":"Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1638-8604","authenticated-orcid":false,"given":"Ina Verena","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Clinical Immunology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6915-9896","authenticated-orcid":false,"given":"Rafaela","family":"Rawinski","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Clinical Immunology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Kramann","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Clinical Immunology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2889-5371","authenticated-orcid":false,"given":"Tammo","family":"Ostendorf","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Clinical Immunology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ute","family":"Raffetseder","sequence":"additional","affiliation":[{"name":"Department of Nephrology and Clinical Immunology, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2444","DOI":"10.1161\/CIRCULATIONAHA.108.800011","article-title":"Acute kidney injury is associated with increased long-term mortality after cardiothoracic surgery","volume":"119","author":"Hobson","year":"2009","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/S0002-9343(98)00058-8","article-title":"Independent association between acute renal failure and mortality following cardiac surgery","volume":"104","author":"Chertow","year":"1998","journal-title":"Am. 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