Dominant-negative NFKBIA mutation promotes IL-1? production causing hepatic disease with severe immunodeficiency.

ABSTRACT: Although IKK-? has previously been shown as a negative regulator of IL-1? secretion in mice, this role has not been proven in humans. Genetic studies of NF-?B signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-?B pathway in suppressing IL-1? 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 I?B? variant that severely repressed NF-?B activation and downstream cytokine production. Paradoxically, IL-1? 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-1? 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-1? release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1? secretion. Our studies reveal a previously unrecognized role of human I?B? as an essential regulator of canonical NF-?B 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-?B inhibition.

SUBMITTER: Tan EE 

PROVIDER: S-EPMC7598087 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature