GSK-3α/β Activity Negatively Regulates MMP-1/9 Expression to Suppress Mycobacterium tuberculosis Infection

作者：Xinying Zhou, Linmiao Lie, Yao Liang, Hui Xu, Bo Zhu, Yingqi Huang, Lijie Zhang, Zelin Zhang, Qianna Li, Qi Wang, Zhenyu Han, Yulan Huang, Honglin Liu, Shengfeng Hu, Chaoying Zhou, Qian Wen, Li Ma · 发表于：Frontiers in Immunology · 年份：2022 · DOI：10.3389/fimmu.2021.752466 · 被引用次数：9 · 研究领域：Galectins and Cancer Biology、Peptidase Inhibition and Analysis、Cell Adhesion Molecules Research

(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 mammali...