Knockdown of GBP1 inhibits BCG-induced apoptosis in macrophage RAW 264.7 cells via p38/JNK pathway.
Knockdown of GBP1 inhibits BCG-induced apoptosis in macrophage RAW 264.7 cells via p38/JNK pathway.
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DOI：
10.1016/j.meegid.2021.105158
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发表时间：
2021-11
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影响因子：
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通讯作者：
Jianhong Wang;Zhan-Chi Liu;Wu Li;Jialin Yu;Dongtao Zhang
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作者：
Jianhong Wang;Zhan-Chi Liu;Wu Li;Jialin Yu;Dongtao Zhang
结核分枝杆菌（mycobacterium tuberculosis, Mtb）诱导肺泡巨噬细胞凋亡在结核的发病机制中起重要作用。越来越多的证据表明鸟苷酸结合蛋白（gbp）与微生物感染等不同的病理过程有关。然而，GBPs是否能调节Mtb诱导的巨噬细胞凋亡尚不清楚。在这项研究中，我们研究了GBP1在卡介苗感染过程中对RAW 264.7细胞凋亡的潜在影响。结果表明，BCG可诱导巨噬细胞凋亡和GBP1表达上调。此外，我们通过靶向GBP1的小干扰rna探讨了GBP1在bcg诱导的RAW 264.7细胞凋亡中的作用。结果表明，敲低GBP1可减轻bcg诱导的RAW 264.7细胞凋亡。此外，我们发现GBP1的敲低降低了切割- caspase 3和切割- parp -1的水平，同时降低了切割- caspase 9、BAX、细胞色素C和APAF1的水平。这些发现表明，GBP1敲低可以通过内源性凋亡途径阻止bcg诱导的细胞凋亡。此外，卡介苗感染后巨噬细胞线粒体膜电位明显升高，敲低GBP1可缓解这一现象。此外，GBP1的下调也减弱了bcg诱导的巨噬细胞中活性氧的积累。在机制上，GBP1抑制p38/JNK通路靶分子的磷酸化，从而调节bgc感染巨噬细胞的凋亡。综上所述，这些发现揭示了GBP1在介导BCG感染巨噬细胞细胞凋亡中的重要作用，以及其抑制BCG诱导的细胞凋亡的分子机制。
Alveolar macrophage apoptosis induced byMycobacterium tuberculosis(Mtb) plays a significant role in mediating the pathogenesis of tuberculosis. There is growing evidence that guanylate-binding proteins (GBPs) are associated with different pathological processes such as microbial infection. However, it remains unclear whether GBPs can regulate the apoptosis of macrophages induced by Mtb. In this study, we investigated the potential effect of GBP1 on RAW 264.7 cell apoptosis duringBacillus Calmette-Guerin(BCG) infection. The results demonstrated that BCG could induce macrophage apoptosis and GBP1 upregulation. In addition, we explored the role of GBP1 in regulating BCG-induced RAW 264.7 cell apoptosis using small interfering RNAs targeting GBP1. The results showed that knockdown of GBP1 could attenuate BCG-induced apoptosis in RAW 264.7 cells. Moreover, we found that GBP1 knockdown decreased the levels of cleaved-Caspase 3 and cleaved-PARP-1, while decreased those of cleaved-Caspase 9, BAX, Cytochrome C and APAF1. These findings imply that GBP1 knockdown can prevent BCG-induced apoptosis through an endogenous apoptosis pathway. In addition, the mitochondrial membrane potential of macrophages was significantly increased after BCG infection, and GBP1 knockdown could alleviate this phenomenon. Furthermore, downregulation of GBP1 also attenuated BCG-induced accumulation of reactive oxygen species in macrophages. Mechanistically, GBP1 suppressed the phosphorylation of the target molecules in p38/JNK pathway, thus regulating the apoptosis of BGC-infected macrophages. Collectively, these findings reveal a significant role of GBP1 in mediating cell apoptosis in macrophages infected with BCG, and the molecular mechanism underlying its suppressive effect on BCG-induced apoptosis.