AI Article Synopsis
- Mitochondrial damage from environmental toxicants can trigger inflammation through the activation of the NLRP3 inflammasome, which is linked to various inflammatory disorders.
- The study aimed to assess whether mitochondrial toxicants cause this inflammasome activation, using specific organotins to test their effects on macrophage cells.
- Results showed that exposure to the toxicants led to inflammasome formation and impaired mitochondrial function, alongside changes in gene expression and signaling pathways associated with inflammation and apoptosis.
Article Abstract
Background: Mitochondrial function is implicated as a target of environmental toxicants and found in disease or injury models, contributing to acute and chronic inflammation. One mechanism by which mitochondrial damage can propagate inflammation is via activation of the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family, pyrin domain-containing receptor (NLRP)3 inflammasome, a protein complex that processes mature interleukin . plays an important role in the innate immune response and dysregulation is associated with autoinflammatory disorders.
Objective: The objective was to evaluate whether mitochondrial toxicants recruit inflammasome activation and processing.
Method: Murine macrophages (RAW 264.7) exposed to tri-organotins (triethyltin bromide (TETBr), trimethyltin hydroxide (TMTOH), triphenyltin hydroxide (TPTOH), bis(tributyltin)oxide) [Bis(TBT)Ox] were examined for pro-inflammatory cytokine induction. TMTOH and TETBr were examined in RAW 264.7 and bone marrow-derived macrophages for mitochondrial bioenergetics, reactive oxygen species (ROS) production, and inflammasome activation via visualization of aggregate formation, caspase-1 flow cytometry, enzyme-linked immunosorbent assay and Western blots, and microRNA (miRNA) and mRNA arrays.
Results: TETBr and TMTOH induced inflammasome aggregate formation and release in lipopolysaccharide (LPS)-primed macrophages. Mitochondrial bioenergetics and mitochondrial ROS were suppressed. and induction with LPS or challenge was diminished. Differential miRNA and mRNA profiles were observed. Lower targeted cyclic adenosine monophosphate (cAMP)-mediated and AMP-activated protein kinase signaling pathways; higher , , and targeted Wnt beta-catenin signaling, retinoic acid receptor activation, apoptosis, signal transducer and activator of transcription 3, IL-22, IL-12, and IL-10 signaling. Functional enrichment analysis identified apoptosis and cell survival canonical pathways.
Conclusion: Select mitotoxic tri-organotins disrupted murine macrophage transcriptional response to LPS, yet triggered inflammasome activation. The differential response pattern suggested unique functional changes in the inflammatory response that may translate to suppressed host defense or prolong inflammation. We posit a framework to examine immune cell effects of environmental mitotoxic compounds for adverse health outcomes. https://doi.org/10.1289/EHP8314.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086801 | PMC |
| http://dx.doi.org/10.1289/EHP8314 | DOI Listing |
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