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

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) infection is the deadliest infectious disease and a global health problem. Macrophages (M phi s) and neutrophils that can phagocytose Mtb represent the first line of immune response to infection. Glycogen synthase kinase-3 alpha/beta (GSK-3 alpha/beta) represents a regulatory switch in host immune responses. However, the efficacy and molecular mechanisms of how GSK-3 alpha/beta interacts with Mtb infection in M phi s remain undefined. Here, we demonstrated that Mtb infection downregulated GSK-3 alpha/beta activity and promoted matrix metalloproteinase-1 (MMP-1) and MMP-9 expressions in M phi s derived from acute monocytic human leukemia THP-1 cells (THP-1-M phi s). We confirmed the upregulation of MMP-9 expression in tissues of TB patients compared with patients of chronic inflammation (CI). In THP-1-M phi s and C57BL/6 mice, GSK-3 alpha/beta 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-3 alpha/beta silencing significantly increased MMP-1/9 expression and Mtb infection, while overexpression of GSK-3 alpha/beta and constitutive activated GSK-3 alpha/beta mutants significantly reduced MMP-1/9 expression and Mtb infection in THP-1-M phi s. MMP-1/9 silencing reduced Mtb infection, while overexpression of MMP-1/9 promoted Mtb infection in THP-1-M phi s. We further found that GSK-3 alpha/beta inhibition increased Mtb infection and MMP-1/9 expression was blocked by ERK1/2 inhibitor. Additionally, we showed that protein kinase C-delta (PKC-delta) and mammalian target of rapamycin (mTOR) reduced GSK-3 alpha/beta activity and promoted MMP-1/9 production in Mtb-infected THP-1-M phi s. In conclusion, this study suggests that PKC-delta-mTOR axis suppresses GSK-3 alpha/beta 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.

Automated summary

This study reveals the significant role of GSK-3alpha/beta pathway in regulating immune response of macrophages to Mycobacterium tuberculosis infection. It also demonstrates that PKC-delta and mTOR can influence the activation of GSK-3alpha/beta and subsequently regulate the expression of MMP-1/9. These findings provide new insights into the immune escape mechanism of tuberculosis and the crosstalk between critical signaling pathways.