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Medullary thymic epithelial NF-kB-inducing kinase (NIK)/IKK? pathway shapes autoimmunity and liver and lung homeostasis in mice.

ABSTRACT: Aberrant T cell development is a pivotal risk factor for autoimmune disease; however, the underlying molecular mechanism of T cell overactivation is poorly understood. Here, we identified NF-?B-inducing kinase (NIK) and IkB kinase ? (IKK?) in thymic epithelial cells (TECs) as essential regulators of T cell development. Mouse TEC-specific ablation of either NIK or IKK? resulted in severe T cell-mediated inflammation, injury, and fibrosis in the liver and lung, leading to premature death within 18 d of age. NIK or IKK? deficiency abrogated medullary TEC development, and led to breakdown of central tolerance, production of autoreactive T cells, and fatal autoimmune destruction in the liver and lung. TEC-specific ablation of NIK or IKK? also impaired thymic T cell development from the double-negative through the double-positive stages and inhibited peripheral B cell development. These results unravel a hitherto unrecognized essential role of TEC-intrinsic NIK and IKK? pathways in autoimmunity and T cell-instigated chronic liver and lung diseases.

SUBMITTER: Shen H

PROVIDER: S-EPMC6754592 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Medullary thymic epithelial NF-kB-inducing kinase (NIK)/IKKα pathway shapes autoimmunity and liver and lung homeostasis in mice.

Shen Hong H Ji Yewei Y Xiong Yi Y Kim Hana H Zhong Xiao X Jin Michelle G MG Shah Yatrik M YM Omary M Bishr MB Liu Yong Y Qi Ling L Rui Liangyou L

Proceedings of the National Academy of Sciences of the United States of America 20190903 38

Aberrant T cell development is a pivotal risk factor for autoimmune disease; however, the underlying molecular mechanism of T cell overactivation is poorly understood. Here, we identified NF-κB-inducing kinase (NIK) and IkB kinase α (IKKα) in thymic epithelial cells (TECs) as essential regulators of T cell development. Mouse TEC-specific ablation of either NIK or IKKα resulted in severe T cell-mediated inflammation, injury, and fibrosis in the liver and lung, leading to premature death within 18 ...[more]

PMID: 31481626

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Project description:Studies from global loss-of-function mutants suggest that alternative NF-kB downstream of NF-kB inducing kinase (NIK) is a cell-intrinsic negative regulator of osteogenesis. However, the interpretation of the osteoblast and/or osteocyte contribution to the bone phenotype is complicated by simultaneous osteoclast defects in these models. Therefore, we turned to a transgenic mouse model to investigate the direct role of NIK in the osteolineage. Osx-Cre;NT3 animals (NT3-Cre+), which bear a constitutively active NIK allele (NT3) driven by Osx-Cre, were compared to their Cre-negative, Control (Ctrl) littermates. NT3-Cre+ mice had elevated serum P1NP and CTX levels. Despite this high turnover state, microCT showed that constitutive activation of NIK resulted in a net increase in basal bone mass in both cortical and cancellous compartments. Furthermore, NT3-Cre+ mice exhibited a greater anabolic response following mechanical loading compared to controls. We next performed RNA-Seq on non-loaded and loaded tibiae to elucidate possible mechanisms underlying the increased bone anabolism seen in NT3-Cre+ mice. Hierarchical clustering revealed two main transcriptional programs: one loading-responsive and the other NT3 transgene-driven. Gene ontology (GO) analysis indicated a distinct upregulation of receptor, kinase and growth factor activities including Wnts, as well as a calcium-response signature in NT3-Cre+ limbs. The promoters of these GO-term associated genes, including many known to be bone-anabolic, were highly enriched for multiple kB recognition elements (kB-RE) relative to the background frequency in the genome. The loading response in NT3-Cre+ mice substantially overlapped (>90%) with Ctrl. Surprisingly, control animals had 10-fold more differentially expressed genes (DEGs) in response to loading. However, most top DEGs shared between genotypes had a high incidence of multiple kB-RE in their promoters. Therefore, both transcriptional programs (loading-responsive and NT3 transgene-driven) are modulated by NF-kB. Our studies uncover a previously unrecognized role for NF-kB in the promotion of both basal and mechanically-stimulated bone formation.

Dataset Information

Medullary thymic epithelial NF-kB-inducing kinase (NIK)/IKK? pathway shapes autoimmunity and liver and lung homeostasis in mice.

Publications

Medullary thymic epithelial NF-kB-inducing kinase (NIK)/IKKα pathway shapes autoimmunity and liver and lung homeostasis in mice.

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