TREM‐1 induces pyroptosis in cardiomyocytes by activating NLRP3 inflammasome through the SMC4/NEMO pathway

Sepsis often causes cell death via pyroptosis and hence results in septic cardiomyopathy. Triggering receptors expressed in myeloid cells‐1 (TREM‐1) may initiate cellular cascade pathways and, in turn, induce cell death and vital organ dysfunction in sepsis, but the evidence is limited. We set to investigate the role of TREM‐1 on nucleotide‐binding oligomerization domain‐like receptors with pyrin domain‐3 (NLRP3) inflammasome activation and cardiomyocyte pyroptosis in sepsis models using cardiac cell line (HL‐1) and mice. In this study, TREM‐1 was found to be significantly increased in HL‐1 cells challenged with lipopolysaccharide (LPS). Pyroptosis was also significantly increased in the HL‐1 cells challenged with lipopolysaccharide and an NLRP3 inflammasome activator, nigericin. The close interaction between TREM‐1 and structural maintenance of chromosome 4 (SMC4) was also identified. Furthermore, inhibition of TREM‐1 or SMC4 prevented the upregulation of NLRP3 and decreased Gasdermin‐D, IL‐1β and caspase‐1 cleavage. In mice subjected to caecal ligation and puncture, the TREM‐1 inhibitor LR12 decreased the expression of NLRP3 and attenuated cardiomyocyte pyroptosis, leading to improved cardiac function and prolonged survival of septic mice. Our work demonstrates that, under septic conditions, TREM‐1 plays a critical role in cardiomyocyte pyroptosis. Targeting TREM‐1 and its associated molecules may therefore lead to novel therapeutic treatments for septic cardiomyopathy.