{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:32:31Z","timestamp":1790937151867,"version":"4.1.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T00:00:00Z","timestamp":1641945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021171","name":"Basic and Applied Basic Research Foundation of Guangdong Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100021171","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Tuberculosis (TB) caused by <jats:italic>Mycobacterium tuberculosis<\/jats:italic> (Mtb) infection is the deadliest infectious disease and a global health problem. Macrophages (M\u03c6s) and neutrophils that can phagocytose Mtb represent the first line of immune response to infection. Glycogen synthase kinase-3\u03b1\/\u03b2 (GSK-3\u03b1\/\u03b2) represents a regulatory switch in host immune responses. However, the efficacy and molecular mechanisms of how GSK-3\u03b1\/\u03b2 interacts with Mtb infection in M\u03c6s remain undefined. Here, we demonstrated that Mtb infection downregulated GSK-3\u03b1\/\u03b2 activity and promoted matrix metalloproteinase-1 (MMP-1) and MMP-9 expressions in M\u03c6s derived from acute monocytic human leukemia THP-1 cells (THP-1-M\u03c6s). We confirmed the upregulation of MMP-9 expression in tissues of TB patients compared with patients of chronic inflammation (CI). In THP-1-M\u03c6s and C57BL\/6 mice, GSK-3\u03b1\/\u03b2 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\u03b1\/\u03b2 silencing significantly increased MMP-1\/9 expression and Mtb infection, while overexpression of GSK-3\u03b1\/\u03b2 and constitutive activated GSK-3\u03b1\/\u03b2 mutants significantly reduced MMP-1\/9 expression and Mtb infection in THP-1-M\u03c6s. MMP-1\/9 silencing reduced Mtb infection, while overexpression of MMP-1\/9 promoted Mtb infection in THP-1-M\u03c6s. We further found that GSK-3\u03b1\/\u03b2 inhibition increased Mtb infection and MMP-1\/9 expression was blocked by ERK1\/2 inhibitor. Additionally, we showed that protein kinase C-\u03b4 (PKC-\u03b4) and mammalian target of rapamycin (mTOR) reduced GSK-3\u03b1\/\u03b2 activity and promoted MMP-1\/9 production in Mtb-infected THP-1-M\u03c6s. In conclusion, this study suggests that PKC-\u03b4-mTOR axis suppresses GSK-3\u03b1\/\u03b2 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.<\/jats:p>","DOI":"10.3389\/fimmu.2021.752466","type":"journal-article","created":{"date-parts":[[2022,1,12]],"date-time":"2022-01-12T05:15:57Z","timestamp":1641964557000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["GSK-3\u03b1\/\u03b2 Activity Negatively Regulates MMP-1\/9 Expression to Suppress Mycobacterium tuberculosis 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