GSK-3α/β Activity Negatively Regulates MMP-1/9 Expression to Suppress Mycobacterium tuberculosis Infection.
GSK-3α/β Activity Negatively Regulates MMP-1/9 Expression to Suppress Mycobacterium tuberculosis Infection.
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GSK-3α/β 活性负调节 MMP-1/9 表达以抑制结核分枝杆菌感染。
DOI：
10.3389/fimmu.2021.752466
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发表时间：
2021
影响因子：
7.3
通讯作者：
Ma L
中科院分区：
文献类型：
--
作者：
Zhou X;Lie L;Liang Y;Xu H;Zhu B;Huang Y;Zhang L;Zhang Z;Li Q;Wang Q;Han Z;Huang Y;Liu H;Hu S;Zhou C;Wen Q;Ma L
由结核分枝杆菌（Mtb）感染引起的结核病是最致命的传染病，也是一个全球性的健康问题。巨噬细胞（Mφs）和嗜中性粒细胞可以吞噬结核分枝杆菌，它们是对感染的第一线免疫反应。糖原合成酶激酶3α/β (GSK-3α/β)在宿主免疫应答中起调节开关作用。然而，GSK-3α/β与m - φs结核分枝杆菌感染相互作用的效果和分子机制尚不清楚。本研究表明，结核分枝杆菌感染可下调GSK-3α/β活性，促进急性单核细胞白血病THP-1细胞（THP-1- m - φs） m - φs中基质金属蛋白酶-1 （MMP-1）和MMP-9的表达。与慢性炎症（CI）患者相比，我们证实结核患者组织中MMP-9表达上调。在thp -1- m - φs和C57BL/6小鼠中，GSK-3α/β抑制剂SB216763显著增加MMP-1/9的产生，促进Mtb负载，而MMP抑制剂抑制MMP-1/9的表达和Mtb感染。同样，GSK-3α/β沉默显著增加MMP-1/9的表达和Mtb感染，而GSK-3α/β过表达和组成型激活GSK-3α/β突变体显著降低thp -1- m - φ中MMP-1/9的表达和Mtb感染。MMP-1/9沉默可降低Mtb感染，而过表达MMP-1/9可促进thp -1- m - φ细胞的Mtb感染。我们进一步发现GSK-3α/β抑制可增加Mtb感染，并且ERK1/2抑制剂可阻断MMP-1/9的表达。此外，我们发现蛋白激酶C-δ (PKC-δ)和哺乳动物雷帕霉素靶蛋白（mTOR）降低了mtb感染的thp -1- m - φ中GSK-3α/β的活性，并促进了MMP-1/9的产生。综上所述，本研究提示PKC-δ-mTOR轴通过磷酸化- erk1 /2促进MMP-1/9表达，从而抑制GSK-3α/β活化。这些结果揭示了结核分枝杆菌的一种新的免疫逃逸机制和抗结核免疫中这些关键信号通路之间的一种新的串扰。
Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection is the deadliest infectious disease and a global health problem. Macrophages (Mφs) and neutrophils that can phagocytose Mtb represent the first line of immune response to infection. Glycogen synthase kinase-3α/β (GSK-3α/β) represents a regulatory switch in host immune responses. However, the efficacy and molecular mechanisms of how GSK-3α/β interacts with Mtb infection in Mφs remain undefined. Here, we demonstrated that Mtb infection downregulated GSK-3α/β activity and promoted matrix metalloproteinase-1 (MMP-1) and MMP-9 expressions in Mφs derived from acute monocytic human leukemia THP-1 cells (THP-1-Mφs). We confirmed the upregulation of MMP-9 expression in tissues of TB patients compared with patients of chronic inflammation (CI). In THP-1-Mφs and C57BL/6 mice, GSK-3α/β inhibitor SB216763 significantly increased MMP-1/9 production and facilitated Mtb load, while MMP inhibitors blocked MMP-1/9 expression and Mtb infection. Consistently, GSK-3α/β silencing significantly increased MMP-1/9 expression and Mtb infection, while overexpression of GSK-3α/β and constitutive activated GSK-3α/β mutants significantly reduced MMP-1/9 expression and Mtb infection in THP-1-Mφs. MMP-1/9 silencing reduced Mtb infection, while overexpression of MMP-1/9 promoted Mtb infection in THP-1-Mφs. We further found that GSK-3α/β inhibition increased Mtb infection and MMP-1/9 expression was blocked by ERK1/2 inhibitor. Additionally, we showed that protein kinase C-δ (PKC-δ) and mammalian target of rapamycin (mTOR) reduced GSK-3α/β activity and promoted MMP-1/9 production in Mtb-infected THP-1-Mφs. In conclusion, this study suggests that PKC-δ-mTOR axis suppresses GSK-3α/β activation with acceleration of MMP-1/9 expression through phospho-ERK1/2. These results reveal a novel immune escape mechanism of Mtb and a novel crosstalk between these critical signaling pathways in anti-TB immunity.
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影响因子：
5.2
作者：
Parasa VR;Muvva JR;Rose JF;Braian C;Brighenti S;Lerm M
通讯作者：
Lerm M
影响因子：
9.3
作者：
Ong CW;Pabisiak PJ;Brilha S;Singh P;Roncaroli F;Elkington PT;Friedland JS
通讯作者：
Friedland JS
影响因子：
11.2
作者：
Cichocki F;Valamehr B;Bjordahl R;Zhang B;Rezner B;Rogers P;Gaidarova S;Moreno S;Tuininga K;Dougherty P;McCullar V;Howard P;Sarhan D;Taras E;Schlums H;Abbot S;Shoemaker D;Bryceson YT;Blazar BR;Wolchko S;Cooley S;Miller JS
通讯作者：
Miller JS
影响因子：
32.4
作者：
Lei, Cao-Qi;Zhong, Bo;Shu, Hong-Bing
通讯作者：
Shu, Hong-Bing
影响因子：
3.2
作者：
Izzo, AA;Izzo, LS;Majka, S
通讯作者：
Majka, S