Although IKK-β has previously been shown as a negative regulator of IL-1β secretion in mice, this role has not been demonstrated in humans. Genetic studies of NF-κB signalling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-κB pathway in suppression of IL-1β expression. Here, we report an infant displaying clinical pathology comprising neutrophil-mediated auto-inflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation in 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 hyper-IL-1β secretion 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, whilst 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 signalling in the prevention of neutrophilic-dependent auto-inflammatory diseases. We showed that IκBα controls IL-1β secretion through a mechanism of self-limiting post-transcriptional regulation. These findings also highlight a therapeutic potential for IL-1 inhibitors to treat complications arising from systemic NF-κB inhibition.
Enrica Ee Kar Tan, Richard Hopkins, Chrissie K. Lim, Saumya Jamuar, Christina Ong, Koh Cheng Thoon, Mark J.A. Koh, Eun Myoung Shin, Derrick Wen Quan Lian, Madhushanee Weerasooriya, Christopher Z.W Lee, Andreas Alvin Purnomo Soetedjo, Chang Siang Lim, Veronica B. Au, WM Edmond Chua, Hui Yin Lee, Leigh Ann Jones, Sharmy Jennifer James, Nivashini Kaliaperumal, Jeffrey Kwok, Ee Shien Tan, Biju Thomas, Lena Ho, Lynn Wu, Anna-Marie Fairhurst, Florent Ginhoux, Adrian K.K. Teo, Yongliang Zhang, Kok Haur Ong, Weimiao Yu, Byrappa Venkatesh, Vinay Tergaonkar, Bruno Reversade, Keh-Chuang Chin, Ah Moy Tan, Woei Kang Liew, John E. Connolly