Activation of TREM-1 induces endoplasmic reticulum stress through IRE-1α/XBP-1s pathway in murine macrophages
Activation of TREM-1 induces endoplasmic reticulum stress through IRE-1α/XBP-1s pathway in murine macrophages
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TREM-1 的激活通过 IRE-1 α/XBP-1s 通路在小鼠巨噬细胞中诱导内质网应激
DOI：
10.1016/j.molimm.2021.04.023
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发表时间：
2021-05-03
影响因子：
3.6
通讯作者：
Zhu, Zhao-Qiong
中科院分区：
文献类型：
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作者：
Dong, Liang;Tan, Cheng-Wei;Zhu, Zhao-Qiong
越来越多的证据表明，内质网（ER）应激会激活许多疾病中的几种促炎信号通路，包括急性肺损伤（ALI）。我们报道，阻断髓样细胞 1 (TREM-1) 表达的触发受体可以通过抑制脂多糖 (LPS) 诱导的 ALI 小鼠的肺部炎症来预防 ALI。然而，TREM-1 诱导巨噬细胞促炎微环境的分子机制仍不清楚。在此，我们的目的是确定 TREM-1 是否调节由 LPS 诱导的与 ER 应激激活相关的炎症反应。我们发现单克隆激动剂抗体（抗 TREM-1）激活 TREM-1 会增加原代巨噬细胞中 IL-1β、TNF-α 和 IL-6 的 mRNA 和蛋白质水平。抗 TREM-1 抗体的治疗增加了原代巨噬细胞中 ER 应激标记物（ATF6、PERK、IRE-1 α 和 XBP-1s）的表达。而用 ER 应激抑制剂 4-PBA 进行预处理，可显着抑制 ER 应激标志物和促炎细胞因子的表达，并减少 LDH 的释放。此外，STF-083010 抑制 IRE-1 α/XBP-1s 通路的活性可显着减轻抗 TREM-1 抗体处理的巨噬细胞中 IL-1 β、TNF-α 和 IL-6 水平的增加。 XBP-1 沉默减弱了 TREM-1 激活引起的促炎微环境。此外，我们发现用 LR12 阻断 TREM-1 可改善体外和体内 LPS 诱导的 ER 应激。总之，我们得出结论，TREM-1 激活通过巨噬细胞中的 IRE1 α/XBP-1s 通路诱导内质网应激，从而促进促炎微环境。
Increasing evidence suggests that endoplasmic reticulum (ER) stress activates several pro-inflammatory signaling pathways in many diseases, including acute lung injury (ALI). We have reported that blocking triggering receptor expressed on myeloid cells 1 (TREM-1) protects against ALI by suppressing pulmonary inflammation in mice with ALI induced by lipopolysaccharides (LPS). However, the molecular mechanism underlying the TREM-1-induced pro-inflammatory microenvironment in macrophages remains unclearly. Herein, we aimed to determine whether TREM-1 regulates the inflammatory responses induced by LPS associated with ER stress activation. We found that the activation of TREM-1 by a monoclonal agonist antibody (anti-TREM-1) increased the mRNA and protein levels of IL-1 beta, TNF-alpha, and IL-6 in primary macrophages. Treatment of the anti-TREM-1 antibody increased the expression of ER stress markers (ATF6, PERK, IRE-1 alpha, and XBP-1s) in primary macrophages. While pretreatment with 4-PBA, an inhibitor of ER stress, significantly inhibited the expression of ER stress markers and proinflammatory cytokines and reduced LDH release. Furthermore, inhibiting the activity of the IRE-1 alpha/XBP-1s pathway by STF-083010 significantly mitigated the increased levels of IL-1 beta, TNF-alpha and IL-6 in macrophages treated by the anti-TREM-1 antibody. XBP-1 silencing attenuated pro-inflammatory microenvironment evoked by activation of TREM-1. Besides, we found that blockade of TREM-1 with LR12 ameliorated ER stress induced by LPS in vitro and in vivo. In conclusion, we conclude that TREM-1 activation induces ER stress through the IRE1 alpha/XBP-1s pathway in macrophages, contributing to the pro-inflammatory microenvironment.