biostudies-literatureSchmerer NBundesministerium für Bildung und Forschung (Federal Ministry of Education and Research)Deutsche Forschungsgemeinschaft (German Research Foundation)Hessisches Ministerium für Wissenschaft und Kunst (Hessen State Ministry of Higher Education, Research and the Arts)Fritz Thyssen Stiftung (Fritz Thyssen Foundation)4733https://www.ebi.ac.uk/biostudies/studies/S-EPMC12095776biostudies-literatureUnknown16(1)Long noncoding RNAs (lncRNA) are crucial yet underexplored regulators of human immunity. Here we develop GRADR, a method integrating gradient profiling with RNA-binding proteome analysis, to map the protein interactomes of all expressed RNAs in a single experiment to study mechanisms of lncRNA-mediated regulation of human primary macrophages. Applying GRADR alongside CRISPR-multiomics, we reveal a network of NFκB-dependent lncRNAs, including LINC01215, AC022816.1 and ROCKI, which modulate distinct aspects of macrophage immunity, particularly through interactions with mRNA-processing factors, such as hnRNP proteins. We further uncover the function of ROCKI in repressing the messenger of the anti-inflammatory GATA2 transcription factor, thus promoting macrophage activation. Lastly, all data Nature communicationsA searchable atlas of pathogen-sensitive lncRNA networks in human macrophages.PMC12095776PerMed-COPD (01EK2203A)10.21.2.024MNSFB-1213 (Project A01)Deep Legion (031L0288A)CIBSS - EXC-2189 - Project ID 390939984BA 2168/25-1LOEWE/2/13/519/03/06.001(0002)/74SFB-TR-84 (subproject C1)SFB-TR-84 (subproject C10)LOEWE/5/A004/519/06/00.005(0008)/E31TRR 167/2 NeuroMacAillaud MWende SHalder LDMarsico ASteding HJanga HSchmerer NNist AAznaourova MKirschbaum APullamsetti SSNtini ESchmeck BBoldt FSchulte LNRuppert CLinne URossbach OHoffmann JStiewe TUhl MBackofen RJerrentrup LValasarajan CfalseA searchable atlas of pathogen-sensitive lncRNA networks in human macrophages.Long noncoding RNAs (lncRNA) are crucial yet underexplored regulators of human immunity. Here we develop GRADR, a method integrating gradient profiling with RNA-binding proteome analysis, to map the protein interactomes of all expressed RNAs in a single experiment to study mechanisms of lncRNA-mediated regulation of human primary macrophages. Applying GRADR alongside CRISPR-multiomics, we reveal a network of NFκB-dependent lncRNAs, including LINC01215, AC022816.1 and ROCKI, which modulate distinct aspects of macrophage immunity, particularly through interactions with mRNA-processing factors, such as hnRNP proteins. We further uncover the function of ROCKI in repressing the messenger of the anti-inflammatory GATA2 transcription factor, thus promoting macrophage activation. Lastly, all data 2025-01-01T00:00:00Z2025 May2026-06-02T20:45:04.629Z2026-04-20T03:10:48.787ZS-EPMC120957764039930910.1038/s41467-025-60084-x