PAI-1 acts as the main inhibitor of both urokinase type plasminogen activators (uPA) and tissue type plasminogen activators (tPA), which convert plasminogen to plasmin.
#MOTILITY ACTIVATOR ACTIVATOR#
Plasminogen activator inhibitor type 1 (PAI-1), also known as serine protease inhibitor E1, is expressed in various cell types such as adipocytes, glomerular mesangial cells, epithelial cells, vascular endothelial cells, vascular smooth-muscle cells, monocytes/macrophages, and astrocytes. Migration of microglia, via extension of their processes, to the site of inflammation is a key step in the progression of the inflammatory brain diseases. Chronically activated microglia also contribute to neurotoxicity in neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, Huntington’s disease, and multiple sclerosis (MS). Microglia, as phagocytes, engulf invaded pathogens, apoptotic cells, and their debris. Microglia, the resident macrophages of the CNS, constitute the brain’s innate immune system and play a pivotal role in neuroinflammation and host defense against microbial agents. Some of these secreted proteins play important roles in the progression of inflammatory diseases in the brain, and serve as biomarkers that can be used to guide diagnosis and drug therapy. Secretomic analysis has been previously conducted for astrocytes and microglia to determine the profile of the secreted proteins. This may have important implications in the regulation of brain microglial activities in health and disease.Īctivated glial cells secrete a variety of proteins including proinflammatory cytokines, chemokines, and neurotoxic factors under inflammatory or pathological conditions. Our results indicate that glia-derived PAI-1 may regulate microglial migration and phagocytosis in an autocrine or paracrine manner. PAI-1 inhibited microglial engulfment of zymosan particles in a vitronectin- and Toll-like receptor 2/6-dependent manner.
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Moreover, PAI-1 was able to modulate microglial phagocytic activity. PAI-1-mediated microglial migration was independent of protease inhibition, because an R346A mutant of PAI-1 with impaired PA inhibitory activity also promoted microglial migration. PAI-1 also increased microglial migration in vivo when injected into mouse brain. PAI-1 promoted the migration of microglial cells in culture via the low-density lipoprotein receptor-related protein (LRP) 1/Janus kinase (JAK)/signal transducer and activator of transcription (STAT)1 axis.
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The levels of PAI-1 mRNA and protein expression were increased by lipopolysaccharide and interferon-γ stimulation in both microglia and astrocytes. Phagocytic activity was measured by uptake of zymosan particles. Cell migration was evaluated by in vitro scratch-wound healing assay or Boyden chamber assay and an in vivo stab wound injury model.
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Secretion of PAI-1 from glial cultures was detected by ELISA and western blotting analysis. In this study, we identified PAI-1 in the culture medium of mouse mixed glial cells by liquid chromatography and tandem mass spectrometry. However, little is known about the role of PAI-1 in the central nervous system. PAI-1 is also involved in the innate immunity by regulating cell migration and phagocytosis.
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Plasminogen activator inhibitor type 1 (PAI-1) is the primary inhibitor of urokinase type plasminogen activators (uPA) and tissue type plasminogen activators (tPA), which mediate fibrinolysis.