TREM-1 triggers necroptosis of macrophages through mTOR-dependent mitochondrial fission during acute lung injury

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.

Knockdown of KIF23 alleviates the progression of asthma by inhibiting pyroptosis

“…Studies have reported that AURKA, MELK and TOP2A are key genes in the pathogenesis of lung adenocarcinoma, and the high level of MELK is associated with the poor prognosis of lung adenocarcinoma 21. Activation of TREM-1 can mediate mTOR-dependent mitochondrial fission and promote necroptosis of macrophages, thereby exacerbating acute lung injury 22. Moreover, TREM-1 aggravates pulmonary fibrosis by aggravating senescence of mouse alveolar epithelial cells 23.…”

Cigarette Smoke Extract-Treated Mouse Airway Epithelial Cells-Derived Exosomal LncRNA MEG3 Promotes M1 Macrophage Polarization and Pyroptosis in Chronic Obstructive Pulmonary Disease by Upregulating TREM-1 via m6A Methylation

“…Similarly, a previous finding revealed that TREM-1 facilitated NLRP3 inflammasome-mediated microglial pyroptosis by elevating the expression of NLRP3, caspase-1, GSDMD, and GSDMD-N, resulting in aggravated neuroinflammation ( 32 ). A recent study by Zhong et al indicated that TREM-1 activation caused necroptosis of macrophages, thereby fueling inflammation and aggravating acute lung injury ( 33 ). More importantly, compelling evidence suggested that exosomes secreted by CSE-treated MAECs induced M1 macrophage polarization and aggravated CS-induced damage in lung function by enhancing TREM-1 expression ( 12 ).…”

Secretion of related factors and AMPK/PGC-1 α signal pathway by alveolar macrophages in viral acute lung injury

“…Various pathogenic factors inside and outside the lung cause acute uncontrolled inflammatory reactions in lung tissue, resulting in alveolar capillary injury, increased permeability and pulmonary edema, which lead to progressive dyspnea and hypoxemia are the main pathophysiological changes of VALI (12). Alveolar enter the lung tissue, further aggravating the injury of lung tissue and promoting the development of patients with VALI (19). Caspase3 is the most representative pro-apoptotic molecule, and Bcl-2 is an anti-apoptotic molecule, which is closely related to the apoptosis of alveolar macrophages (20).…”