Phthalate drives splenic inflammatory response via activating HSP60/TLR4/NLRP3 signaling axis-dependent pyroptosis

As the most produced phthalate, di-(2-ethylhexyl) phthalate (DEHP) is a widely environmental pollutant primarily used as a plasticizer, which cause the harmful effects on human health. However, the impact of DEHP on spleen and its underlying mechanisms are still unclear. Pyroptosis is a novel form o...

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Published in:Environmental pollution (1987) 2024-04, Vol.346, p.123610-123610, Article 123610
Main Authors: Ge, Xin-Ran, Zhao, Yi, Ren, Hao-Ran, Jiang, Fu-Wei, Liu, Shuo, Lou, Ming, Huang, Yi-Feng, Chen, Ming-Shan, Wang, Jia-Xin, Li, Jin-Long
Format: Article
Language:English
Subjects:
Animals
Chaperonin 60 - pharmacology
Di-(2-ethylhexyl) phthalate
Diethylhexyl Phthalate - toxicity
HSP60
Humans
Inflammasomes - metabolism
Male
Mice
Mice, Inbred ICR
NLR Family, Pyrin Domain-Containing 3 Protein - metabolism
NLRP3
Phthalic Acids
Pyroptosis
Spleen - metabolism
Splenic inflammatory response
Toll-Like Receptor 4 - metabolism
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Summary:As the most produced phthalate, di-(2-ethylhexyl) phthalate (DEHP) is a widely environmental pollutant primarily used as a plasticizer, which cause the harmful effects on human health. However, the impact of DEHP on spleen and its underlying mechanisms are still unclear. Pyroptosis is a novel form of cell death induced by activating NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasomes and implicated in pathogenesis of numerous inflammatory diseases. The current study aimed to explore the impact of DEHP on immune inflammatory response in mouse spleen. In this study, the male ICR mice were treated with DEHP (200 mg/kg) for 28 days. Here, DEHP exposure caused abnormal pathohistological and ultrastructural changes, accompanied by inflammatory cells infiltration in mouse spleen. DEHP exposure arouse heat shock response that involves increase of heat shock proteins 60 (HSP60) expression. DEHP also elevated the expressions of toll-like receptor 4 (TLR4) and myeloid differentiation protein 88 (MyD88) proteins, as well as the activation of NF-κB pathway. Moreover, DEHP promoted NLRP3 inflammasome activation and triggered NLRP3 inflammasome-induced pyroptosis. Mechanistically, DEHP drives splenic inflammatory response via activating HSP60/TLR4/NLRP3 signaling axis-dependent pyroptosis. Our findings reveal that targeting HSP60-mediated TLR4/NLRP3 signaling axis may be a promising strategy for inflammatory diseases treatment. Phthalate drives splenic inflammatory response via activating HSP60/TLR4/NLRP3 signaling axis-dependent pyroptosis. [Display omitted] •Di-(2-ethylhexyl) phthalate (DEHP) induced the activation of heat shock proteins.•DEHP caused TLR4/MyD88-mediated inflammatory injury in the spleen.•DEHP triggered splenic inflammatory response-dependent pyroptosis.•DEHP activated heat shock protein 60 (HSP60)-mediated TLR4/MyD88/NF-κB pathway.
ISSN:0269-7491
1873-6424
DOI:10.1016/j.envpol.2024.123610