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 (IL)-1β. IL-1β 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 IL-1β 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, IL-1β enzyme-linked immunosorbent assay and Western blots, and microRNA (miRNA) and mRNA arrays. RESULTS TETBr and TMTOH induced inflammasome aggregate formation and IL-1β release in lipopolysaccharide (LPS)-primed macrophages. Mitochondrial bioenergetics and mitochondrial ROS were suppressed. Il1a and Il1b induction with LPS or LPS+ATP challenge was diminished. Differential miRNA and mRNA profiles were observed. Lower miR-151-3p targeted cyclic adenosine monophosphate (cAMP)-mediated and AMP-activated protein kinase signaling pathways; higher miR-6909-5p, miR-7044-5p, and miR-7686-5p 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.

中文翻译：

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评估线粒体功能和炎症巨噬细胞激活暴露于选择线粒体Tri-Organotin化合物的小鼠巨噬细胞中的关联。

背景技术线粒体功能被认为是环境毒物的靶标，并且在疾病或损伤模型中被发现，从而导致急性和慢性炎症。线粒体损伤可以传播炎症的一种机制是通过激活核苷酸结合寡聚化域（NOD）样受体（NLR）家族，含吡喃域的受体（NLRP）3炎性小体（一种处理成熟白介素（IL）的蛋白质复合物） ）-1β。IL-1β在先天免疫反应中起重要作用，并且调节异常与自身炎症性疾病有关。目的目的是评估线粒体毒物是否募集炎性体激活和IL-1β加工。方法鼠巨噬细胞（RAW 264.7）暴露于三有机锡（溴化三乙基锡（TETBr），氢氧化三甲基锡（TMTOH），检查了氢氧化三苯锡（TPTOH），双（三丁基锡）氧化物[Bis（TBT）Ox]促炎性细胞因子的诱导。通过观察聚集体形成，caspase-1流式细胞术，IL-1β酶联免疫吸附试验和结合物，在RAW 264.7和骨髓来源的巨噬细胞中检查了TMTOH和TETBr的线粒体生物能，活性氧（ROS）产生和炎症小体活化。 Western印迹以及microRNA（miRNA）和mRNA阵列。结果TETBr和TMTOH诱导了脂多糖（LPS）引发的巨噬细胞中炎性体聚集物的形成和IL-1β的释放。线粒体生物能学和线粒体ROS被抑制。LPS或LPS + ATP攻击的Il1a和Il1b诱导减少。观察到不同的miRNA和mRNA谱。较低的miR-151-3p靶向环磷酸腺苷（cAMP）介导和AMP激活的蛋白激酶信号传导途径；更高的miR-6909-5p，miR-7044-5p和miR-7686-5p靶向Wntβ-catenin信号传导，视黄酸受体激活，细胞凋亡，信号转导和转录激活因子3，IL-22，IL-12和IL-10信号传导。功能富集分析确定了凋亡和细胞存活的经典途径。结论选择具有线粒体毒性的三有机锡可破坏鼠巨噬细胞对LPS的转录反应，但会触发炎症小体活化。差异反应模式提示炎症反应中独特的功能变化，可能转变为抑制宿主防御或延长炎症。我们提出了一个框架，以检查环境化学毒性化合物对健康不利影响的免疫细胞作用。https://doi.org/10.1289/EHP8314。