TREM‐1 induces pyroptosis in cardiomyocytes by activating NLRP3 inflammasome through the SMC4/NEMO pathway
TREM‐1 induces pyroptosis in cardiomyocytes by activating NLRP3 inflammasome through the SMC4/NEMO pathway
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DOI：
10.1111/febs.16644
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发表时间：
2022-10
期刊：
影响因子：
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通讯作者：
Zilong Yang;Xiaoyan Pan;Xiaoxia Wu;Qiuyun Lin;Yongxia Chen;Shuting Cai;Yuanli Zhang;Z. Mai;Niall Ahmad;D. Ma;L. Deng
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文献类型：
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作者：
Zilong Yang;Xiaoyan Pan;Xiaoxia Wu;Qiuyun Lin;Yongxia Chen;Shuting Cai;Yuanli Zhang;Z. Mai;Niall Ahmad;D. Ma;L. Deng
脓毒症通常通过焦亡引起细胞死亡，因此导致脓毒性心肌病。髓样细胞中表达的触发受体-1（TREM-1）可能启动细胞级联途径，进而诱导脓毒症中的细胞死亡和重要器官功能障碍，但证据有限。我们使用心脏细胞系（HL-1）和小鼠研究TREM-1对脓毒症模型中具有pyrin结构域-3（NLRP 3）炎性小体活化和心肌细胞焦亡的核苷酸结合寡聚化结构域样受体的作用。在这项研究中，发现TREM-1在脂多糖（LPS）攻击的HL-1细胞中显著增加。在用脂多糖和NLRP 3炎性体激活剂尼日利亚菌素攻击的HL-1细胞中，细胞凋亡也显著增加。还鉴定了TREM-1与4号染色体结构维持（SMC4）之间的密切相互作用。此外，TREM-1或SMC 4的抑制阻止了NLRP 3的上调，并降低了Gasdermin-D、IL-1 β和caspase-1的裂解。在盲肠结扎和穿孔的小鼠中，TREM-1抑制剂LR12降低了NLRP 3的表达，减弱了心肌细胞的焦亡，从而改善了心脏功能，延长了脓毒症小鼠的存活时间。我们的工作表明，在脓毒症条件下，TREM-1在心肌细胞焦亡中起着关键作用。因此，靶向TREM-1及其相关分子可能会为脓毒性心肌病带来新的治疗方法。
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.