TLR2 signaling directs NO-dependent MMP-9 induction in mouse microglia.
Microglia are neural immune cells that produce pro-inflammatory proteins in the central nervous system. Dysregulation of microglia gene expression is linked to the chronic brain inflammation and the neurological disorders. Matrix metalloproteinase-9 (MMP-9) is a pro-inflammatory protease that regulates the neurotoxicity of glial cells in the brain and spinal cord. Recent studies showed the accumulation of MMP-9 at microglia-rich plaques associates with neurodegenerative diseases. However, the regulatory mechanism of MMP-9 expression in microglia inflammation is still unknown. Here we show that oxidized low-density lipoprotein (oxLDL) induces the expression and secretion of Pro-MMP-9 (92kDa) via TLR2 signaling pathway in mouse microglial cells. Depletion of TLR2 or its signaling mediators MyD88/TRAF6 blocks the agonist-induced MMP-9 expression. In addition, TLR2-dependent nitric oxide (NO) synthesis is also required for endogenous Pro-MMP-9 expression and secretion. Cell death assay indicates that the neurotoxicity of microglia is regulated by endogenous NO and TLR2 signaling pathway. Our findings establish a pathophysiological link between oxLDL and MMP-9 expression in microglia-related neuroinflammation.
Department of Neurology, The Affiliated Jiangyin Hospital of Southest University Medial College, 163 Shoushan Road, Jiangyin 214400, China. Electronic address: yanbai307@gmail.com.
Yanyan
Y
Bai
Department of Neurology, The Affiliated Jiangyin Hospital of Southest University Medial College, 163 Shoushan Road, Jiangyin 214400, China.
Zufu
Z
Zhu
Department of Neurology, The Affiliated Jiangyin Hospital of Southest University Medial College, 163 Shoushan Road, Jiangyin 214400, China.
Zhiqiang
Z
Gao
Department of Neurology, The Affiliated Jiangyin Hospital of Southest University Medial College, 163 Shoushan Road, Jiangyin 214400, China. Electronic address: yukong605229931@gmail.com.
Yu
Y
Kong
D000818:Animals; D017209:Apoptosis; D004790:Enzyme Induction; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000633:toxicity; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D011498:Protein Precursors / Q000096:biosynthesis; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*
D008077:Lipoproteins, LDL; D011498:Protein Precursors; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; C099252:oxidized low density lipoprotein; D009569:Nitric Oxide; D020780:Matrix Metalloproteinase 9
MMP-9; Microglia; Neuroinflammation; Nitric oxide; TLR2 signaling pathway; oxLDL