Palmitate-Induced Mmp-9 Expression in the Human Monocytic Cells: Significance in Metabolic Inflammation

Abstract Matrix metalloproteinase (MMP)-9 is predominantly produced by monocytes/macrophages and directs the infiltration of circulatory immune cells into the adipose tissue through damage of vascular endothelial basement membrane. Obese individuals are known to have increased MMP-9 plasma levels and MMP-9 is reported to play an important role in obesity-mediated adipose tissue inflammation. Since in obesity, the levels of circulatory free fatty acid palmitate are increased and modulate the expression of inflammatory mediators, the role of palmitate in the regulation of MMP-9 remains unclear. Therefore, we determined whether palmitate could induce MMP-9 production, and if so, which signaling pathway(s) were involved. Here, we provide the evidence that palmitate induces MMP-9 expression at both mRNA and protein levels in human monocytic cells (P<0.05). Increased NF-κB/AP-1 activity (P<0.05) was also observed in palmitate-treated THP-1 cells. Palmitate-induced MMP-9 secretion was markedly suppressed either by neutralizing anti-TLR-4 antibody or by inhibiting clathrin-mediated endocytosis. Furthermore, MyD88−/− THP-1 cells did not express MMP-9 in response to palmitate treatment. Genetic silencing of TLR4 by siRNA also abrogated the palmitate-induced up-regulation of MMP-9. Altogether, these results show that palmitate induces TLR4-dependent activation of MMP-9 gene expression, which requires the recruitment of MyD88 leading to activation of NF-kB/AP1 transcription factors. Thus, our findings suggest that the palmitate-induced MMP-9 secretion might be an underlying mechanism of its increased levels in obesity and related metabolic inflammation.