{"doi":"10.1016/j.ebiom.2024.105452","title":"NF-κB c-Rel is a critical regulator of TLR7-induced inflammation in psoriasis","abstract":"BACKGROUND: Nuclear factor kappa B (NF-κB) c-Rel is a psoriasis susceptibility locus, however mechanisms underlying c-Rel transactivation during disease are poorly understood. Inflammation in psoriasis can be triggered following Toll-like Receptor 7 (TLR7) signalling in dendritic cells (DCs), and c-Rel is a critical regulator of DC function. Here, we studied the mechanism of TLR7-induced c-Rel-mediated inflammation in DCs. METHODS: The overall expression of c-Rel was analysed in skin sections from patients with psoriasis in human transcriptomics datasets as well as the imiquimod-induced psoriasis mouse model. The function of c-Rel in DCs following TLR7 stimulation was determined by c-Rel CRISPR/Cas9 knockout DC2.4 immortalised cells and primary bone marrow derived dendritic cells from c-Rel knockout C57BL6/J mice. FINDINGS: c-Rel is highly expressed in lesional skin of patients with psoriasis and TLR7-induced psoriatic lesions in mice. c-Rel deficiency protected mice from the disease, and specifically compromised TLR7-induced, and not TLR9- or TLR3-induced, inflammation in dendritic cells. Mechanistically, c-Rel deficiency disrupted activating NF-κB dimers and allowed binding of inhibitory NF-κB homodimers to the IL-1β and IL-6 promoters thus inhibiting their expression. This functionally compromises the ability of c-Rel deficient DCs to induce Th17 polarisation, which is critical in psoriasis pathogenesis. INTERPRETATION: Our findings reveal that c-Rel is a key regulator of TLR7-mediated dendritic cell-dependent inflammation, and that targeting c-Rel-dependent signalling could prove an effective strategy to dampen excessive inflammation in TLR7-related skin inflammation. FUNDING: A complete list of funding sources that contributed to this study can be found in the Acknowledgements section.","journal":"EBioMedicine","year":2024,"id":426728,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9636,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1180498,"name":"Nandini Sarkar","orcid":"0000-0001-6817-0629","position":1,"is_corresponding":false},{"id":1226762,"name":"Jordan D. Cress","orcid":null,"position":2,"is_corresponding":false},{"id":327818,"name":"Tristan J de Jesus","orcid":null,"position":3,"is_corresponding":false},{"id":1226763,"name":"A. Vadlakonda","orcid":null,"position":4,"is_corresponding":false},{"id":708348,"name":"Joshua T Centore","orcid":null,"position":5,"is_corresponding":false},{"id":1226153,"name":"Alexis D. Griffith","orcid":"0000-0002-1599-623X","position":6,"is_corresponding":false},{"id":570308,"name":"Bethany R. Rohr","orcid":"0000-0003-1027-5203","position":7,"is_corresponding":false},{"id":376945,"name":"Thomas S. McCormick","orcid":"0000-0002-3294-0326","position":8,"is_corresponding":false},{"id":441928,"name":"Kevin D. Cooper","orcid":"0000-0002-1986-3602","position":9,"is_corresponding":false},{"id":326799,"name":"Parameswaran Ramakrishnan","orcid":"0000-0002-1314-827X","position":10,"is_corresponding":false},{"id":698505,"name":"Angela Rose Liu","orcid":"0000-0001-7148-5605","position":0,"is_corresponding":true}],"reference_count":110,"raw_metadata":null,"created_at":"2026-07-19T01:58:42.796720Z","pmid":"39586195","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}