TREM-1 governs NLRP3 inflammasome activation of macrophages by firing up glycolysis in acute lung injury

The triggering receptor expressed on myeloid cells-1 (TREM-1) is a pro-inflammatory immune receptor potentiating acute lung injury (ALI). However, the mechanism of TREM-1-triggered inflammation response remains poorly understood. Here, we showed that TREM-1 blocking attenuated NOD-, LRR-and pyrin domain-containing 3 (NLRP3) inflammasome activation and glycolysis in LPS-induced ALI mice. Then, we observed that TREM-1 activation enhanced glucose consumption, induced glycolysis, and inhibited oxidative phosphorylation in macrophages. Specifically, inhibition of glycolysis with 2-deoxyglucose diminished NLRP3 inflammasome activation of macrophages triggered by TREM-1. Hypoxia-inducible factor-1a (HIF-1 alpha) is a critical transcriptional regulator of glycolysis. We further found that TREM-1 activation facilitated HIF-1 alpha accumulation and translocation to the nucleus via the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Inhibiting mTOR or HIF-1 alpha also suppressed TREM-1-induced metabolic reprogramming and NLRP3/caspase-1 activation. Overall, the mTOR/HIF-1 alpha/glycolysis pathway is a novel mechanism underlying TREM-1- governed NLRP3 inflammasome activation. Therapeutic targeting of the mTOR/HIF-1 alpha/glycolysis pathway in TREM-1- activated macrophages could be beneficial for treating or preventing inflammatory diseases, such as ALI.

Automated summary

The activation of the triggering receptor expressed on myeloid cells-1 (TREM-1) can potentiate acute lung injury (ALI) and induce inflammation, but the underlying mechanism is unclear. This study found that blocking TREM-1 can attenuate the activation of NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome and glycolysis in LPS-induced ALI mice. Furthermore, TREM-1 activation enhances glycolysis and inhibits oxidative phosphorylation in macrophages, and this effect is dependent on the hypoxia-inducible factor-1a (HIF-1 alpha)/mTOR/glycolysis pathway. Inhibiting mTOR or HIF-1 alpha can suppress TREM-1-induced metabolic reprogramming and NLRP3/caspase-1 activation. These findings reveal a novel mechanism of TREM-1-mediated NLRP3 inflammasome activation through the mTOR/HIF-1 alpha/glycolysis pathway.