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

Abstract Background Necroptosis of macrophage plays an essential role in amplifying intrapulmonary inflammation during acute lung injury (ALI). However, the molecular mechanism that triggers 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 role of TREM-1 in macrophage fate during ALI needs 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. Mechanistically, macrophages were treated with RIPK3 inhibitor (GSK872), GTPase dynamin-related protein 1 (DRP1) inhibitor (Mdivi-1), or the nutrient-sensing mechanistic/mammalian target of rapamycin complex (mTOR) inhibitor (Rapamycin) to investigate macrophage necroptosis induced by TREM-1. Results We first observed that blockade of TREM-1 attenuated macrophage necroptosis in LPS-induced ALI mice. In vitro, TREM-1 activation induced necroptosis of macrophages. mTOR has been previously linked to macrophage polarization and migration. Interestingly, we identified a previously unknown role of mTOR in regulating TREM-1-mediated mitochondrial fission, mitophagy, and necroptosis. Moreover, TREM-1 activation promoted DRP1Ser616 phosphorylation via mTOR signaling, leading to excessive mitochondrial fission-mediated necroptosis of macrophages, and finally exacerbated ALI. Conclusion In this study, we reported TREM-1 acted as a necroptotic stimulus of macrophage, which fueled inflammation and aggravated ALI. We also provided compelling evidence suggesting mTOR-dependent mitochondrial fission as underpinnings 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.