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

Abstract

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.

RNA-seq Analysis of the BCG Vaccine in a Humanized Mouse Model

“…Some studies have found that inhibiting the expression of MMP-1/9 inhibits M. tuberculosis infection [20]. However, among the DEGs induced by BCG screened in this study, we observed no differential expression of the above five isoforms.…”

RNA Expression of MMP12 Is Strongly Associated with Inflammatory Bowel Disease and Is Regulated by Metabolic Pathways in RAW 264.7 Macrophages

“…Nevertheless, opposite to that which was commonly observed for cytokines and chemokines [ 41 , 42 , 43 ], the inhibition of mTOR signaling tended to upregulate the expression of MMPs. In fact, it was recently described that the attenuation of mTOR in THP-1 macrophages by rapamycin or silica dust induced the expression of relevant metalloproteinases, such as MMP1 and MMP9 [ 44 , 45 ]. Consistently with this, the exacerbation in the induction of a well-defined detrimental factor such as MMP12 by the activation of AMPK is rather unexpected, since the upregulation of this pathway typically counteracts excessive inflammatory responses in macrophages by mediating the effects of anti-inflammatory cytokines or inhibiting the production of pro-inflammatory mediators such as TNF-α and IL6 [ 46 , 47 , 48 ].…”

Leptin Induces MMP-1 Expression Through the RhoA/ERK1/2/NF-κB Axis in Human Intervertebral Disc Cartilage Endplate-Derived Stem Cells

“…For instance, in human chondrosarcoma cells and articular chondrocytes, IL-1β and TNF-α have been found to increase MMP-1 expression. 40 In another scenario, mechanical stretch has been shown to induce MMP-1 expression in human keratoconus fibroblasts, highlighting its significance in corneal extracellular matrix remodeling. 41 Furthermore, upregulation of MMP-1 has been observed in Mycobacterium tuberculosis-infected macrophages, where MMP-1 appears to promote M. tuberculosis infection.…”