Lithium chloride suppresses LPS‐mediated matrix metalloproteinase‐9 expression in macrophages through phosphorylation of GSK‐3β

Abstract

Abnormal degradation of matrix components due to dysregulated expression of matrix metalloproteinase (MMP)-9 in macrophages has been linked to progression of acute cerebral ischemia and atherosclerosis. We report that lithium chloride (LiCl) or CHIR99021, inhibitors of Wnt signaling pathway, enhance phosphorylation of glycogen synthase kinase-3beta and suppress lipopolysaccharide-mediated upregulation of MMP-9 expression in murine macrophage RAW264.7 cells in a dose-dependent manner. Suppression of MMP-9 expression by LiCl or CHIR99021 did not result after inhibition of kinases involved in NFκB or AP-1 family proteins, but from changes in the activity of histone deacetylases. Beneficial effects on atherosclerosis or cerebral ischemia in animal studies caused by LiCl may be in part explained by the suppression of MMP-9 gene expression.

Gene Expression Dynamics at the Neurovascular Unit During Early Regeneration After Cerebral Ischemia/Reperfusion Injury in Mice

“…Furthermore, pharmacological induction of β-Catenin by CHIR99021 was able to reactivate matured cardiomyocytes and therefore suggested as a future approach for regeneration after myocardial infarction (Fan et al, 2018). The same compound has been reported to suppress MMP9 release from macrophages in vitro (Kim et al, 2015) which also implies a potential use in BBB protection after cerebral I/R injury. Our current results might help in designing future in vivo assessment of this approach according to the biphasic regulation of the Wnt signaling cascade.…”

<p>Lithium chloride with immunomodulatory function for regulating titanium nanoparticle-stimulated inflammatory response and accelerating osteogenesis through suppression of MAPK signaling pathway</p>

“…Even though many studies have indicated that LiCl can regulate some biological processes, such as inflammation, apoptosis, and glycogen synthesis, the mechanisms involved in these processes are not well understood 18–20. Furthermore, it has been reported that LiCl enhances osteogenesis in wear particle-induced osteolysis via Glycogen synthase kinase-3β (GSK-3β) signaling pathway inhibition and attenuates osteoclastogenesis by suppressing the nuclear factor-kappa B (NF-κB) pathway 19,21. In addition to these biological processes, the effects of LiCl in regulating inflammation in different immune cell models, especially macrophages, in the context of inflammatory diseases, have also been explored 22–24.…”

A reduced risk of stroke with lithium exposure in bipolar disorder: a population‐based retrospective cohort study

“…Matrix metalloproteinase (MMP)‐9 was associated with abnormal degradation of the extracellular matrix when its production by macrophages was deregulated. Lithium treatment was found to suppress MMP‐9 gene expression and reduce the level of this metalloproteinase , thereby reducing plaque instability. Vascular smooth muscle cell (VSMC) proliferation and migration in the intima of the arterial wall also play an important role in atheroma progression .…”