2. Academic Validation
  3. ALK-JNK signaling promotes NLRP3 inflammasome activation and pyroptosis via NEK7 during Streptococcus pneumoniae infection

ALK-JNK signaling promotes NLRP3 inflammasome activation and pyroptosis via NEK7 during Streptococcus pneumoniae infection

  • Mol Immunol. 2023 Mar 29;157:78-90. doi: 10.1016/j.molimm.2023.03.016.
Xia Wang 1,  Yan Zhao 2,  Dan Wang 2,  Chang Liu 3,  Zhi Qi 4,  Huixin Tang 2,  Yashan Liu 2,  Shiqi Zhang 2,  Yali Cui 5,  Yingying Li 6,  Ruiqing Liu 7,  Yanna Shen 8
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China.
  • 2 School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, PR China.
  • 3 School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, PR China; Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou 571199, PR China.
  • 4 Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou 571199, PR China.
  • 5 Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China; Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Chengdu, Sichuan 610041, PR China.
  • 6 Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, PR China; Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Chengdu, Sichuan 610041, PR China. Electronic address: [email protected].
  • 7 School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, PR China; The Third Central Hospital of Tianjin, 83 Jintang Road, Hedong District, Tianjin 300170, PR China; Tianjin Key Laboratory of Extracorporeal Life Support for Critical Diseases, Tianjin 300170, PR China; Artificial Cell Engineering Technology Research Center, Tianjin 300170, PR China; Tianjin Institute of Hepatobiliary Disease, Tianjin 300170, PR China. Electronic address: [email protected].
  • 8 School of Medical Laboratory, Tianjin Medical University, Tianjin 300203, PR China; Key Laboratory of Emergency and Trauma of Ministry of Education, Hainan Medical University, Haikou 571199, PR China. Electronic address: [email protected].
PMID: 37001294 DOI: 10.1016/j.molimm.2023.03.016
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.

Keywords

ALK; JNK; NEK7; NLRP3 inflammasome; Pyroptosis; Streptococcus pneumoniae.

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