Dominant-negative NFKBIA mutation promotes IL-1β production causing hepatic disease with severe immunodeficiency
Enrica E.K. Tan, … , Woei Kang Liew, John E. Connolly
Enrica E.K. Tan, … , Woei Kang Liew, John E. Connolly
Published August 4, 2020
Citation Information: J Clin Invest. 2020;130(11):5817-5832. https://doi.org/10.1172/JCI98882.
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Research Article Immunology Inflammation

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

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.

Authors

Enrica E.K. Tan, Richard A. Hopkins, Chrissie K. Lim, Saumya S. Jamuar, Christina Ong, Koh C. Thoon, Mark J.A. Koh, Eun Mong Shin, Derrick W.Q. Lian, Madhushanee Weerasooriya, Christopher Z.W. Lee, Andreas Alvin Pumomo Soetedjo, Chang Siang Lim, Veonice B. Au, Edmond Chua, Hui Yin Lee, Leigh Ann Jones, Sharmy S. James, Nivashini Kaliaperumal, Jeffery Kwok, Ee Shien Tan, Biju Thomas, Lynn Xue Wu, Lena Ho, Anna Marie Fairhurst, Florent Ginhoux, Adrian K.K. Teo, Yong Liang Zhang, Kok Huar Ong, Weimiao Yu, Byrappa Venkatesh, Vinay Tergaonkar, Bruno Reversade, Keh Chuang Chin, Ah Moy Tan, Woei Kang Liew, John E. Connolly

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Figure 4

Enhanced IL-1β production by BMDMs from LysM-cre+ NfkbiaL34P conditional-knockin mice.

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Enhanced IL-1β production by BMDMs from LysM-cre+ NfkbiaL34P conditional...
(A and B) ELISA measurement of IL-1β (A) and IL-6 (C) production in supernatants from WT and LysM-cre NfkbiaL34P BMDMs after 6, 9, 12, and 24 hours of stimulation with LPS (100 ng/mL). qPCR measurement of Il1b (B) and Il6 (D) transcript expression levels in RNA from WT and LysM-cre NfkbiaL34P BMDMs after 6, 12, and 24 hours of stimulation with LPS (100 ng/mL), shown as the 2-ΔΔCt fold change relative to an unstimulated sample (0 hours) and normalized to Actb. (E) Representative confocal microscopic images of NF-κB p65 nuclear translocation, represented by colocalization with DAPI, in BMDMs from WT and LysM-cre NfkbiaL34P mice stimulated for 60 minutes with LPS (100 ng/mL) or left unstimulated. Original magnification, ×20. Scale bars: 10 μm. Data are representative of 3 experiments and indicate the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA with a Holm-Šidák multiple-comparisons test.