NF-κB-Inducing Kinase (NIK) Governs the Mitochondrial Respiratory Capacity, Differentiation, and Inflammatory Status of Innate Immune Cells. NF-κB-Inducing Kinase (NIK) Governs the Mitochondrial Respiratory Capacity, Differentiation, and Inflammatory Status of Innate Immune Cells

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) functions that impair 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, indicative of systemic inflammation. These findings suggest that NIK is required for the metabolic rewiring of mitochondrial respiration that is critical for balancing pro- and anti-inflammatory myeloid immune cell functions. 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. Overall design: 1 million WT and NIK KO bone marrow derrived macrophages from 2 mice per genotype and treatment were treated with PBS or 20ng/mL IL-4 for 6 hours

NF-κB诱导激酶（NF-κB-Inducing Kinase, NIK）是非经典NF-κB通路激活的必需分子，参与调控免疫、发育及疾病进程中的多种生物学过程。尽管近期研究已阐明NIK在适应性免疫细胞与肿瘤细胞代谢中的重要功能，但天然免疫细胞中NIK在代谢驱动的炎症反应中的作用仍不明确。本研究证实，NIK缺陷型骨髓来源巨噬细胞存在线粒体依赖性代谢及氧化磷酸化（oxidative phosphorylation, OXPHOS）功能缺陷，进而无法获得促修复、抗炎表型。后续实验显示，NIK敲除小鼠的髓系细胞出现异常偏倚，表现为血液、骨髓及脂肪组织中嗜酸性粒细胞、单核细胞与巨噬细胞群体的稳态失衡。进一步研究发现，NIK缺陷的血液单核细胞在体外对细菌脂多糖呈现高反应性，且肿瘤坏死因子α（TNF-α）产生水平升高，提示存在系统性炎症状态。这些发现表明，NIK对于线粒体呼吸的代谢重编程是必需的，而该过程是平衡促炎与抗炎髓系免疫细胞功能的关键环节。总体而言，本研究揭示了NIK此前未被认知的功能：作为分子稳态调节器（molecular rheostat）精准调控天然免疫中的免疫代谢过程，并提示代谢功能异常可能是由NIK表达或活性异常所介导的炎症疾病的重要驱动因素。实验设计概况：每基因型与处理组取2只小鼠的骨髓来源巨噬细胞，各100万个野生型（WT）与NIK敲除（KO）细胞，分别用磷酸盐缓冲液（PBS）或20ng/mL白细胞介素4（IL-4）处理6小时