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 (92 kDa) 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.