{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T01:35:26Z","timestamp":1791941726952,"version":"4.3.4"},"reference-count":64,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T00:00:00Z","timestamp":1760918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Peri-implantitis is an inflammatory condition affecting the hard and soft tissues surrounding osseointegrated implants, characterized by progressive alveolar bone destruction. The long non-coding RNA Negative Regulator of Interferon Response (lncRNA <jats:italic>NRIR<\/jats:italic>) is widely recognized as a biomarker for certain autoimmune diseases and participates in their pathogenesis. However, our previous studies revealed significant upregulation of <jats:italic>NRIR<\/jats:italic> in peri-implantitis, suggesting its potential role in peri-implantitis. In peri-implantitis lesions, there is often a substantial infiltration of M1 macrophages. Thus, this study investigated the regulatory role and underlying mechanisms of <jats:italic>NRIR<\/jats:italic> in macrophage polarization during peri-implantitis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Transcriptome sequencing analysis revealed radical S-adenosyl methionine domain containing 2 (<jats:italic>RSAD2<\/jats:italic>) as an <jats:italic>NRIR<\/jats:italic>-interacting mRNA in macrophages. Using siRNA gene knockdown technology, we suppressed <jats:italic>NRIR<\/jats:italic> and <jats:italic>RSAD2<\/jats:italic> expression in M1 macrophages derived from THP-1 cells. Subsequently, we employed RT-qPCR, Western blot, flow cytometry, and immunofluorescence staining to assess the levels of inflammatory cytokines and M1 macrophage-associated markers, aiming to elucidate the involvement of <jats:italic>NRIR<\/jats:italic>\/<jats:italic>RSAD2<\/jats:italic>\/NF-\u03baB axis in macrophage polarization. Supernatants from <jats:italic>NRIR<\/jats:italic>-knockdown macrophages were collected to prepare the culture medium for bone marrow mesenchymal stem cells (BMSCs). The expression of osteogenic-related factors in BMSCs was evaluated through RT-qPCR, Western blot, Alkaline phosphatase (ALP) activity, and alizarin red S (ARS) staining. Furthermore, a rat peri-implantitis model was established, and the degree of peri-implant tissue inflammation and bone loss was assessed using micro-CT scanning and immunohistochemistry after treatment with various macrophage supernatants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>NRIR<\/jats:italic> knockdown reduced <jats:italic>RSAD2<\/jats:italic> expression and suppressed activation of the NF-\u03baB pathway, consequently decreasing inflammatory cytokines and M1 macrophage-associated cytokine expression in THP-1 macrophages. Functionally, <jats:italic>NRIR<\/jats:italic> knockdown in macrophages promoted osteogenic differentiation of BMSCs. In vivo experiments showed that supernatants derived from <jats:italic>NRIR<\/jats:italic>-knockdown macrophages resulted in reduced inflammatory infiltration, diminished bone resorption, and increased expression of osteogenesis-related factors.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>This study demonstrates that <jats:italic>NRIR<\/jats:italic> functions as a pro-inflammatory modulator in peri-implantitis by activating M1 macrophages through the <jats:italic>RSAD2<\/jats:italic>\/NF-\u03baB axis, providing novel insights into peri-implantitis pathogenesis that may inform future preventive and therapeutic strategies.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1650984","type":"journal-article","created":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T04:14:26Z","timestamp":1760933666000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["LncRNA NRIR inhibits osteogenesis 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