1. NLRX1 modulates differentially NLRP3 inflammasome activation and NF-κB signaling during Fusobacterium nucleatum infection
- Author
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Hung, Shu-Chen, Huang, Pei-Rong, Almeida-da-Silva, Cássio Luiz Coutinho, Atanasova, Kalina R, Yilmaz, Ozlem, and Ojcius, David M
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Dental/Oral and Craniofacial Disease ,Infectious Diseases ,Aetiology ,2.1 Biological and endogenous factors ,CARD Signaling Adaptor Proteins ,Caspase 1 ,Cell Nucleus ,Cells ,Cultured ,Epithelial Cells ,Fusobacterium Infections ,Fusobacterium nucleatum ,Gene Expression ,Gingiva ,Humans ,Inflammasomes ,Interleukin-8 ,Mitochondria ,Mitochondrial Proteins ,NLR Family ,Pyrin Domain-Containing 3 Protein ,RNA ,Small Interfering ,Reactive Oxygen Species ,Signal Transduction ,Transcription Factor RelA ,Oral ,Periodontal ,Innate immunity ,Inflammation ,Microbiology ,Immunology ,Medical Microbiology - Abstract
NOD-like receptors (NLRs) play a large role in regulation of host innate immunity, yet their role in periodontitis remains to be defined. NLRX1, a member of the NLR family that localizes to mitochondria, enhances mitochondrial ROS (mROS) generation. mROS can activate the NLRP3 inflammasome, yet the role of NLRX1 in NLRP3 inflammasome activation has not been examined. In this study, we revealed the mechanism by which NLRX1 positively regulates ATP-induced NLRP3 inflammasome activation through mROS in gingival epithelial cells (GECs). We found that depletion of NLRX1 by shRNA attenuated ATP-induced mROS generation and redistribution of the NLRP3 inflammasome adaptor protein, ASC. Furthermore, depletion of NLRX1 inhibited Fusobacterium nucleatum infection-activated caspase-1, suggesting that it also inhibits the NLRP3 inflammasome. Conversely, NLRX1 also acted as a negative regulator of NF-κB signaling and IL-8 expression. Thus, NLRX1 stimulates detection of the pathogen F. nucleatum via the inflammasome, while dampening cytokine production. We expect that commensals should not activate the inflammasome, and NLRX1 should decrease their ability to stimulate expression of pro-inflammatory cytokines such as IL-8. Therefore, NLRX1 may act as a potential switch with regards to anti-microbial responses in healthy or diseased states in the oral cavity.
- Published
- 2018