Human cytomegalovirus infection activates NLRP3 inflammasome by releasing mtDNA into the cytosol in human THP‐1 cells

Abstract

Human cytomegalovirus (HCMV) infection of monocytes results in the production of inflammatory cytokine through inflammasome. However, the mechanism of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation in HCMV infection remains unclear. In this study, HCMV infection promoted the increase of mitochondrial fusion and caused mitochondrial dysfunction in THP‐1 cells, including excessive reactive oxygen species production and decreased mitochondrial membrane potential (Δψm). Meanwhile, the expression of mitochondrial DNA (mtDNA)‐binding protein TFAM (transcription factor A, mitochondrial) was decreased and 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 a 3 h treatment with MCC950, an 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 the IL‐1β process after HCMV infection. mtDNA‐deficient cells showed a limited ability to produce NLRP3 and process IL‐1β after HCMV infection. 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.

Mesenchymal Stem Cell-Derived Exosomes Attenuate Murine Cytomegalovirus-Infected Pneumonia via NF-κB/NLRP3 Signaling Pathway

“…Previous studies have demonstrated the crucial role of the NF-κB and NLRP3 signaling pathways in the inflammatory response induced by CMV [ 7 , 8 ]. In order to investigate the impact of mMSC-exos on the activation of NLRP3, we evaluated the expression of relevant components within the NLRP3 signaling pathway.…”

“…Inflammatory pathways are dysregulated in CMV pneumonia, leading to hyperinflammation characterized by macrophage activation and neutrophil recruitment [ 30 , 31 , 32 ]. The NF-κB/NLRP3 inflammasome signaling pathways play a critical role in the lung immune response, contributing to both the initiation and progression of pneumonia [ 7 , 8 , 33 , 34 ]. CMV can directly activate the NF-κB pathway, resulting in the expression and assembly of NLRP3, which leads to an over-release of pro-inflammatory cytokines and chemokines [ 7 , 8 , 33 ].…”

“…The NF-κB/NLRP3 inflammasome signaling pathways play a critical role in the lung immune response, contributing to both the initiation and progression of pneumonia [ 7 , 8 , 33 , 34 ]. CMV can directly activate the NF-κB pathway, resulting in the expression and assembly of NLRP3, which leads to an over-release of pro-inflammatory cytokines and chemokines [ 7 , 8 , 33 ]. Therefore, these pathways are strongly correlated and form a complex network of inflammatory cascades that contribute to tissue damage [ 1 ].…”

“…CMV interacts with its host immune system and contributes to immune activation and hyperinflammation. CMV infection activates the NF-κB and NLRP3 signaling pathways, promoting the production of various pro-inflammatory mediators, including interleukin-1β (IL-1β), IL-6, tumor necrosis factor alpha (TNFα), and interferons [ 7 , 8 ]. These inflammatory mediators play crucial roles in the inflammatory process underlying lung tissue injury [ 9 ].…”

Investigating the Nexus of NLRP3 Inflammasomes and COVID-19 Pathogenesis: Unraveling Molecular Triggers and Therapeutic Strategies

“…Cytomegalovirus infection also shows signs that NLRP3 may play an antiviral effect. NLRP3 activation is accompanied by the release of pro-inflammatory cytokines, which helps to improve the virus clearance ability of immune cells [ 16 ]. This suggests that NLRP3 may play a similar regulatory role in different types of viral infections.…”