Mitochondria have a multitude of functions, including energy generation and cell signaling. Recent evidence suggests that mitochondrial dynamics (i.e. the balance between mitochondrial fission and fusion) also regulate immune functions. Here, we reveal that lipopolysaccharide (LPS) stimulation increases mitochondrial numbers in mouse bone marrow‐derived macrophages (BMMs) and human monocyte‐derived macrophages. In BMMs, this response requires Toll‐like receptor 4 (Tlr4) and the TLR adaptor protein myeloid differentiation primary response 88 (MyD88) but is independent of mitochondrial biogenesis. Consistent with this phenomenon being a consequence of mitochondrial fission, the dynamin‐related protein 1 (Drp1) GTPase that promotes mitochondrial fission is enriched on mitochondria in LPS‐activated macrophages and is required for the LPS‐mediated increase in mitochondrial numbers in both BMMs and mouse embryonic fibroblasts. Pharmacological agents that skew toward mitochondrial fusion also abrogated this response. LPS triggered acute Drp1 phosphorylation at serine 635 (S635), followed by sustained Drp1 dephosphorylation at serine 656 (S656), in BMMs. LPS‐induced S656 dephosphorylation was abrogated in MyD88‐deficient BMMs, suggesting that this post‐translational modification is particularly important for Tlr4‐inducible fission. Pharmacological or genetic targeting of Tlr4‐inducible fission had selective effects on inflammatory mediator production, with LPS‐inducible mitochondrial fission promoting the expression and/or secretion of a subset of inflammatory mediators in BMMs and mouse embryonic fibroblasts. Thus, triggering of Tlr4 results in MyD88‐dependent activation of Drp1, leading to inducible mitochondrial fission and subsequent inflammatory responses in macrophages.

中文翻译：

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脂多糖促进巨噬细胞中依赖 Drp1 的线粒体裂变和相关的炎症反应。

线粒体具有多种功能，包括能量产生和细胞信号传导。最近的证据表明线粒体动力学（即线粒体裂变和融合之间的平衡）也调节免疫功能。在这里，我们揭示了脂多糖 (LPS) 刺激增加了小鼠骨髓衍生巨噬细胞 (BMM) 和人类单核细胞衍生巨噬细胞的线粒体数量。在 BMM 中，这种反应需要 Toll 样受体 4 (Tlr4) 和 TLR 衔接蛋白髓样分化初级反应 88 (MyD88)，但与线粒体生物发生无关。与这种现象是线粒体裂变的结果一致，促进线粒体裂变的动力蛋白相关蛋白 1 (Drp1) GTPase 在 LPS 激活的巨噬细胞的线粒体上富集，并且是 LPS 介导的 BMM 和小鼠胚胎成纤维细胞线粒体数量增加所必需的。偏向线粒体融合的药理学试剂也消除了这种反应。在 BMM 中，LPS 触发了丝氨酸 635 (S635) 处的急性 Drp1 磷酸化，然后是丝氨酸 656 (S656) 处的持续 Drp1 去磷酸化。LPS 诱导的 S656 去磷酸化在MyD88缺陷的 BMM，表明这种翻译后修饰对于 Tlr4 诱导的裂变特别重要。Tlr4 诱导裂变的药理学或基因靶向对炎症介质的产生具有选择性影响，LPS 诱导的线粒体裂变促进 BMM 和小鼠胚胎成纤维细胞中炎症介质子集的表达和/或分泌。因此，Tlr4 的触发导致 Drp1 的 MyD88 依赖性激活，导致巨噬细胞中可诱导的线粒体裂变和随后的炎症反应。