ArticleThe Journal of clinical investigation2020
Dominant-negative NFKBIA mutation promotes IL-1β production causing hepatic disease with severe immunodeficiency.
Article in The Journal of clinical investigation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 21 citations in OpenAlex.
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- ITGAM-macrophage modulation as a potential strategy for treating neutrophilic Asthma: insights from bioinformatics analysis and in vivo experiments.Apoptosis : an international journal on programmed cell death · 2024Article
- Cellular models in autoinflammatory disease research.Clinical & translational immunology · 2024Review
- Investigation of immune-related diseases using patient-derived induced pluripotent stem cells.Inflammation and regeneration · 2023Review
- High-Dose Vitamin B6 (Pyridoxine) Displays Strong Anti-Inflammatory Properties in Lipopolysaccharide-Stimulated Monocytes.Biomedicines · 2023Article
- N6-methyladenosine-methylomic landscape of lung tissues of mice with chronic obstructive pulmonary disease.Frontiers in immunology · 2023Article
- Identification of key biomarkers and signaling pathways and analysis of their association with immune cells in immunoglobulin A nephropathy.Central-European journal of immunology · 2022Article
- Nutritional immunomodulation of Atlantic salmon response toFrontiers in molecular biosciences · 2022Article
- Induced Pluripotent Stem Cell-Derived Monocytes/Macrophages in Autoinflammatory Diseases.Frontiers in immunology · 2022Review
- Integrating Network Pharmacology and Experimental Validation to Investigate the Effects and Mechanism ofFrontiers in pharmacology · 2020Article
- Silencing lncRNA TUG1 Alleviates LPS-Induced Mouse Hepatocyte Inflammation by Targeting miR-140/TNF.Frontiers in cell and developmental biology · 2020Article
- Bioinformatics-Based Approach for Exploring the Immune Cell Infiltration Patterns in Alzheimer's Disease and Determining the Intervention Mechanism of Liuwei Dihuang Pill.Dose-response : a publication of International Hormesis SocietyArticle
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Authors and funding
37 authors at 8 institutions in 5 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although IKK-β has previously been shown as a negative regulator of IL-1β secretion in mice, this role has not been proven in humans. Genetic studies of NF-κB signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-κB pathway in suppressing IL-1β expression. Here, we report an infant with a clinical pathology comprising neutrophil-mediated autoinflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation of NFKBIA, resulting in a L34P IκBα variant that severely repressed NF-κB activation and downstream cytokine production. Paradoxically, IL-1β secretion was elevated in the patient's stimulated leukocytes, in her induced pluripotent stem cell-derived macrophages, and in murine bone marrow-derived macrophages containing the L34P mutation. The patient's hypersecretion of IL-1β correlated with activated neutrophilia and liver fibrosis with neutrophil accumulation. Hematopoietic stem cell transplantation reversed neutrophilia, restored a resting state in neutrophils, and normalized IL-1β release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1β secretion. Our studies reveal a previously unrecognized role of human IκBα as an essential regulator of canonical NF-κB signaling in the prevention of neutrophil-dependent autoinflammatory diseases. These findings also highlight the therapeutic potential of IL-1 inhibitors in treating complications arising from systemic NF-κB inhibition.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.