2. Academic Validation
  3. Human Cytomegalovirus infection activates NLRP3 inflammasome by releasing mtDNA into cytosol in human THP-1 cells

Human Cytomegalovirus infection activates NLRP3 inflammasome by releasing mtDNA into cytosol in human THP-1 cells

  • Microbiol Immunol. 2023 Mar 18. doi: 10.1111/1348-0421.13063.
Xi Xu 1 2 3 4,  Junwen Cai 2 3,  Xiaoming Wang 1 2 3,  Yutian Lu 1 2 3,  Binhan Guo 1 2 3,  Meimei Lai 1 2 3,  Linhua Lan 2,  Ying Peng 2 3,  Xiaoqun Zheng 1 2 3
Affiliations

Affiliations

  • 1 The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 2 School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
  • 3 The Key Laboratory of Laboratory Medicine, Ministry of Education, Wenzhou, Zhejiang, China.
  • 4 Department of Clinical Laboratory, Wenzhou People's Hospital, The Third Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou, China.
PMID: 36932814 DOI: 10.1111/1348-0421.13063
Abstract

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.

Keywords

Human Cytomegalovirus; NLRP3; TFAM; mitochondria; mtDNA.

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