Human Cytomegalovirus infection activates NLRP3 inflammasome by releasing mtDNA into cytosol in human THP-1 cells.
Xi XuJunwen CaiXiaoming WangYutian LuBinhan GuoMeimei LaiLinhua LanYing PengXiao-Qun ZhengPublished in: Microbiology and immunology (2023)
Human Cytomegalovirus (HCMV) infection of monocytes results in the production of inflammatory cytokine through inflammasome. However, the mechanism of NLRP3 inflammasome activation in HCMV infection still remains unclear. In this study, HCMV infection promoted the increase of mitochondrial fusion and caused mitochondrial dysfunction in THP-1 cells, including excessive ROS production and decreased mitochondrial membrane potential. Meanwhile, the expression of mtDNA-binding protein TFAM (transcription factor A, mitochondrial) was decreased and mitochondrial DNA (mtDNA) content in the cytoplasm was increased. Knockdown of TFAM caused an increase in mtDNA copy number in the cytoplasm and resulted in elevated NLRP3 expression, active caspase-1 and mature IL-1β. After 3-hour treatment with MCC950, a NLRP3 inhibitor, the increase of cleaved caspase-1 and mature IL-1β were suppressed. Besides, overexpression of TFAM inhibited the expression of NLRP3, cleaved caspase-1 and mature IL-1β. In addition, knockdown of NLRP3 inhibited IL-1β process after HCMV infecion. MtDNA-deficient cells showed a limited ability to produce NLRP3 and process IL-1β after HCMV infecion. In conclusion, HCMV infection of THP-1 cells resulted in decreased mitochondrial TFAM protein expression and increased mtDNA release into the cytoplasm, which eventually led to the activation of NLRP3 inflammasome. This article is protected by copyright. All rights reserved.
Keyphrases
- nlrp inflammasome
- mitochondrial dna
- copy number
- induced apoptosis
- oxidative stress
- cell cycle arrest
- cell death
- binding protein
- poor prognosis
- endoplasmic reticulum stress
- endothelial cells
- transcription factor
- genome wide
- signaling pathway
- dna methylation
- physical activity
- cell proliferation
- gene expression
- climate change
- reactive oxygen species
- weight gain
- pi k akt
- epstein barr virus
- risk assessment
- smoking cessation
- combination therapy
- replacement therapy