{"doi":"10.1101/2022.08.06.503047","title":"NF-κB-Inducing Kinase (NIK) Governs the Mitochondrial Respiratory Capacity, Differentiation, and Inflammatory Status of Innate Immune Cells","abstract":"Abstract NF-κB-Inducing Kinase (NIK), which is essential for the activation of the noncanonical NF-κB pathway, regulates diverse processes in immunity, development, and disease. While recent studies have elucidated important functions of NIK in adaptive immune cells and cancer cell metabolism, the role of NIK in metabolic-driven inflammatory responses in innate immune cells remains unclear. Here, we demonstrate that NIK-deficient bone marrow-derived macrophages exhibit defects in mitochondrial-dependent metabolism and oxidative phosphorylation (OXPHOS), which impairs the acquisition of a pro-repair, anti-inflammatory phenotype. Subsequently, NIK-deficient mice exhibit skewing of myeloid cells characterized by aberrant eosinophil, monocyte, and macrophage cell populations in the blood, bone marrow, and adipose tissue. Furthermore, NIK-deficient blood monocytes display hyperresponsiveness to bacterial lipopolysaccharide and elevated TNFα production ex vivo. These findings suggest that NIK governs metabolic rewiring, which is critical for balancing pro- and anti-inflammatory myeloid immune cell function. Overall, our work highlights a previously unrecognized role for NIK as a molecular rheostat that fine-tunes immunometabolism in innate immunity and suggests that metabolic dysfunction may be an important driver of inflammatory diseases caused by aberrant NIK expression or activity. Key Points NIK-deficient macrophages exhibit impaired mitochondrial oxidative phosphorylation NIK-deficient mice have more inflammatory myeloid cells in blood and bone marrow NIK-dependent metabolic rewiring shapes pro- and anti-inflammatory innate immunity","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":304000,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":996854,"name":"Ashley Winters","orcid":null,"position":1,"is_corresponding":false},{"id":256476,"name":"Raquel Sitcheran","orcid":"0000-0001-8916-9707","position":2,"is_corresponding":false},{"id":571201,"name":"A. Phillip West","orcid":"0000-0003-2884-6895","position":3,"is_corresponding":false},{"id":931733,"name":"Justin Keeney","orcid":"0000-0003-1748-0971","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-19T00:32:28.468841Z","pmid":null,"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":[]}