NEK7 interacts with NLRP3 to modulate the pyroptosis in inflammatory bowel disease via NF-κB signaling

• Published in: Cell death & disease 2019-12, Vol.10 (12), p.906-12, Article 906
• Main Authors: Chen, Xueliang, Liu, Ganglei, Yuan, Yuanyuan, Wu, Guotao, Wang, Shalong, Yuan, Lianwen
• Format: Article
• Language: English
• Subjects: 14/28; 14/34; 631/80; 64/60; 692/699; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Caspase-1; Cell Biology; Cell Culture; Cell Line; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Epithelial Cells - metabolism; Epithelial Cells - ultrastructure; Female; Gastrointestinal tract; Gene expression; HEK293 Cells; Humans; Immunology; Inflammasomes; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - genetics; Inflammatory Bowel Diseases - metabolism; Inflammatory Bowel Diseases - pathology; Intestine; Life Sciences; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Macrophages; Mice, Inbred C57BL; Models, Biological; NF-kappa B - metabolism; NF-κB protein; NIMA-Related Kinases - genetics; NIMA-Related Kinases - metabolism; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Protein Binding - drug effects; Pyroptosis; Pyroptosis - drug effects; RelA protein; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; TLR4 protein; Toll-Like Receptor 4 - metabolism; Toll-like receptors; Transcription; Transcription, Genetic - drug effects
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-019-2157-1

Inflammatory bowel disease (IBD) is one of the most common diseases in the gastrointestinal tract related to aberrant inflammation. Pyroptosis, which is characterized by inflammasome formation, the activation of caspase-1, and the separation of the N- and C-terminals of GSDMD, might be related to IBD pathogenesis. NEK7 is an important component of the NLRP3 inflammasome in macrophages. We attempted to investigate the mechanism of NEK7 interacting with NLRP3 to modulate the pyroptosis in IBD. NEK7 mRNA and protein expression and pyroptosis-associated factors, including Caspase-1 (p45, p20), NLRP3, and GSDMD, were upregulated in IBD tissues. NEK7 knockdown abolish ATP + LPS-induced pyroptosis in vitro and improved DSS-induced chronic colitis in vivo. NEK7 interacted with NLRP3, as revealed by Co-IP and GST pull-down assays, to exert its effects. Moreover, short-term LPS treatment alone induced no significant changes in NEK7 protein level. TLR4/NF-κB signaling in MODE-K cells could be activated by LPS treatment. LPS-induced NEK7 upregulation could be significantly reversed by JSH-23, an inhibitor of p65. Furthermore, LUC and ChIP assays revealed that RELA might activate the transcription of NEK7 via targeting its promoter region. LPS-induced TLR4/NF-κB activation causes an increase in NEK7 expression by RELA binding NEK7 promoter region. In conclusion, NEK7 interacts with NLRP3 to modulate NLRP3 inflammasome activation, therefore modulating the pyroptosis in MODE-K cells and DSS-induced chronic colitis in mice. We provide a novel mechanism of NEK7-NLRP3 interaction affecting IBD via pyroptosis.