TREM-1 通过急性肺损伤中 mTOR 依赖性线粒体分裂触发巨噬细胞的坏死性凋亡。
TREM-1 triggers necroptosis of macrophages through mTOR-dependent mitochondrial fission during acute lung injury.
机构信息
Department of Physiology, School of Basic Medical Science, Central South University, Changsha, 410078, Hunan, China.
Department of Physiology, Hunan University of Medicine, Huaihua, China.
出版信息
J Transl Med. 2023 Mar 6;21(1):179. doi: 10.1186/s12967-023-04027-4.
BACKGROUND
Necroptosis of macrophages is a necessary element in reinforcing intrapulmonary inflammation during acute lung injury (ALI). However, the molecular mechanism that sparks macrophage necroptosis is still unclear. Triggering receptor expressed on myeloid cells-1 (TREM-1) is a pattern recognition receptor expressed broadly on monocytes/macrophages. The influence of TREM-1 on the destiny of macrophages in ALI requires further investigation.
METHODS
TREM-1 decoy receptor LR12 was used to evaluate whether the TREM-1 activation induced necroptosis of macrophages in lipopolysaccharide (LPS)-induced ALI in mice. Then we used an agonist anti-TREM-1 Ab (Mab1187) to activate TREM-1 in vitro. Macrophages were treated with GSK872 (a RIPK3 inhibitor), Mdivi-1 (a DRP1 inhibitor), or Rapamycin (an mTOR inhibitor) to investigate whether TREM-1 could induce necroptosis in macrophages, and the mechanism of this process.
RESULTS
We first observed that the blockade of TREM-1 attenuated alveolar macrophage (AlvMs) necroptosis in mice with LPS-induced ALI. In vitro, TREM-1 activation induced necroptosis of macrophages. mTOR has been previously linked to macrophage polarization and migration. We discovered that mTOR had a previously unrecognized function in modulating TREM-1-mediated mitochondrial fission, mitophagy, and necroptosis. Moreover, TREM-1 activation promoted DRP1 phosphorylation through mTOR signaling, which in turn caused surplus mitochondrial fission-mediated necroptosis of macrophages, consequently exacerbating ALI.
CONCLUSION
In this study, we reported that TREM-1 acted as a necroptotic stimulus of AlvMs, fueling inflammation and aggravating ALI. We also provided compelling evidence suggesting that mTOR-dependent mitochondrial fission is the underpinning of TREM-1-triggered necroptosis and inflammation. Therefore, regulation of necroptosis by targeting TREM-1 may provide a new therapeutic target for ALI in the future.
背景
巨噬细胞的坏死性凋亡是急性肺损伤（ALI）期间增强肺内炎症的必要因素。然而，引发巨噬细胞坏死性凋亡的分子机制尚不清楚。髓样细胞触发受体-1（TREM-1）是广泛表达于单核细胞/巨噬细胞上的一种模式识别受体。TREM-1 对 ALI 中巨噬细胞命运的影响需要进一步研究。
方法
使用 TREM-1 诱饵受体 LR12 来评估 LPS 诱导的 ALI 中 TREM-1 的激活是否诱导巨噬细胞坏死性凋亡。然后，我们使用激动型抗-TREM-1 Ab（Mab1187）在体外激活 TREM-1。用 GSK872（RIPK3 抑制剂）、Mdivi-1（DRP1 抑制剂）或雷帕霉素（mTOR 抑制剂）处理巨噬细胞，以研究 TREM-1 是否能诱导巨噬细胞发生坏死性凋亡，以及该过程的机制。
结果
我们首先观察到，阻断 TREM-1 可减轻 LPS 诱导的 ALI 中小鼠肺泡巨噬细胞（AlvMs）的坏死性凋亡。在体外，TREM-1 的激活诱导了巨噬细胞的坏死性凋亡。mTOR 先前与巨噬细胞极化和迁移有关。我们发现，mTOR 在调节 TREM-1 介导的线粒体裂变、线粒体自噬和坏死性凋亡方面具有以前未知的功能。此外，TREM-1 激活通过 mTOR 信号促进 DRP1 磷酸化，进而导致过量的线粒体分裂介导的巨噬细胞坏死性凋亡，从而加重 ALI。
结论
在这项研究中，我们报道 TREM-1 作为 AlvMs 的坏死性凋亡刺激物，促进炎症并加重 ALI。我们还提供了有力的证据表明，mTOR 依赖性线粒体裂变是 TREM-1 触发的坏死性凋亡和炎症的基础。因此，通过靶向 TREM-1 调节坏死性凋亡可能为未来的 ALI 提供新的治疗靶点。
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