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- Title
TREM-1 triggers necroptosis of macrophages through mTOR-dependent mitochondrial fission during acute lung injury.
- Authors
Zhong, Wen-Jing; Zhang, Jun; Duan, Jia-Xi; Zhang, Chen-Yu; Ma, Sheng-Chao; Li, Yu-Sheng; Yang, Nan-Shi-Yu; Yang, Hui-Hui; Xiong, Jian-Bing; Guan, Cha-Xiang; Jiang, Zhi-Xing; You, Zhi-Jian; Zhou, Yong
- Abstract
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 DRP1Ser616 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.
- Subjects
LUNG injuries; MACROPHAGES; LUNGS; MITOCHONDRIA; PATTERN perception receptors; MTOR inhibitors
- Publication
Journal of Translational Medicine, 2023, Vol 21, Issue 1, p1
- ISSN
1479-5876
- Publication type
Article
- DOI
10.1186/s12967-023-04027-4