ALK-JNK signaling promotes NLRP3 inflammasome activation and pyroptosis via NEK7 during Streptococcus pneumoniae infection. (May 2023)

• Record Type: Journal Article
• Authors: Wang, Xia; Zhao, Yan; Wang, Dan; Liu, Chang; Qi, Zhi; Tang, Huixin; Liu, Yashan; Zhang, Shiqi; Cui, Yali; Li, Yingying; Liu, Ruiqing; Shen, Yanna
• Is Part Of: Molecular immunology. Volume 157(2023)
• Page Start: 78
• Page End: 90
• Publication Date: 2023-05
• Subjects: ALK -- JNK -- NEK7 -- NLRP3 inflammasome -- Pyroptosis -- Streptococcus pneumoniae; Immunochemistry -- Periodicals; Molecular biology -- Periodicals; Immunochemistry -- Periodicals; Allergy and Immunology -- Periodicals; Molecular Biology -- Periodicals; Immunochimie -- Périodiques; Biologie moléculaire -- Périodiques; Immunochemistry; Molecular biology; Periodicals; Electronic journals; 571.96
• DOI: 10.1016/j.molimm.2023.03.016
• Languages: English
• ISSNs: 0161-5890

Abstract

Abstract: Streptococcus pneumoniae ( S. pneumoniae ), a clinically important pathogen worldwide, causes serious invasive diseases, such as pneumonia, otitis media, and meningitis. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome, an important component of the innate immune system, plays a key role in defense against pathogen infection; however the specific activation mechanism induced by S. pneumoniae infection is not fully understood. Here, primary mouse macrophages were selected as the in vitro cell model, and the effect of kinases on S. pneumoniae infection-induced NLRP3 inflammasome activation was investigated in vivo and in vitro using the western blot/RT-PCR/Co-IP/immunofluorescence staining/ELISA with or without kinase inhibitor or siRNA pretreatment. In this study, we found that the formation of the NEK7-NLRP3 complex significantly increased during S. pneumoniae infection and that anaplastic lymphoma kinase (ALK) and Jun N-terminal kinase (JNK) were phosphorylated rapidly. ALK and JNK inhibitors significantly reduced the ability of bacterial killing, the gene expression of NLRP3 inflammasome, the formation of apoptosis-associated speck-like protein containing caspase-recruitment domain (ASC) specks and the NEK7-NLRP3 complex, which in turn decreased the activation level of NLRP3 inflammasome-associated molecules and the maturation of interleukin-1β (IL-1β). In addition, ALK regulated the phosphorylation of JNK. Interestingly, the ALK/JNK/NEK7-NLRP3 signaling pathway is also involved in regulating pyroptosis and IL-1β secretion triggered by S. pneumoniae infection. In conclusion, our data suggest, for the first time, that the ALK/JNK/NEK7-NLRP3 signaling pathway may play an important role in NLRP3 inflammasome activation and pyroptosis and consequently regulate the host immune response upon S. pneumoniae infection. Graphical Abstract: The signaling pathway of NLRP3 inflammasome activation and pyroptosis during S. pneumoniae infection. ga1 Highlights: NEK7 is vital in Streptococcus pneumoniae infection-induced NLRP3 inflammasome activation. ALK/JNK signaling pathway activates NLRP3 inflammasome during Streptococcus pneumoniae infection. ALK/JNK/NEK7-NLRP3 axis is involved in Streptococcus pneumoniae induced pyroptosis.