| First Author | Tan EE | Year | 2020 |
| Journal | J Clin Invest | Volume | 130 |
| Issue | 11 | Pages | 5817-5832 |
| PubMed ID | 32750042 | Mgi Jnum | J:302495 |
| Mgi Id | MGI:6508172 | Doi | 10.1172/JCI98882 |
| Citation | Tan EE, et al. (2020) Dominant-negative NFKBIA mutation promotes IL-1beta production causing hepatic disease with severe immunodeficiency. J Clin Invest 130(11):5817-5832 |
| abstractText | Although IKK-beta has previously been shown as a negative regulator of IL-1beta secretion in mice, this role has not been proven in humans. Genetic studies of NF-kappaB signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-kappaB pathway in suppressing IL-1beta 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 IkappaBalpha variant that severely repressed NF-kappaB activation and downstream cytokine production. Paradoxically, IL-1beta 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-1beta 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-1beta release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1beta secretion. Our studies reveal a previously unrecognized role of human IkappaBalpha as an essential regulator of canonical NF-kappaB 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-kappaB inhibition. |
