Abstract
Serum amyloid A (SAA) is an uremic toxin and acute phase protein. It accumulates under inflammatory conditions associated with high cardiovascular morbidity and mortality in patients with sepsis or end-stage renal disease (ESRD). SAA is an apolipoprotein of the high-density lipoprotein (HDL). SAA accumulation turns HDL from an anti-inflammatory to a pro-inflammatory particle. SAA activates monocyte chemoattractant protein-1 (MCP-1) in vascular smooth muscle cells. However, the SAA receptor-mediated signaling pathway in vascular cells is poorly understood. Therefore, the SAA-mediated signaling pathway for MCP-1 production was investigated in this study. The SAA-induced MCP-1 production is dependent on the activation of TLR2 and TLR4 as determined by studies with specific receptor antagonists and agonists or siRNA approach. Experiments were confirmed in tissues from TLR2 knockout, TLR4 deficient and TLR2 knock-out/TLR4 deficient mice. The intracellular signaling pathway is IκBα and subsequently NFκB dependent. The MCP-1 production induced by SAA-enriched HDL and HDL isolated from septic patients with high SAA content is also TLR2 and TLR4 dependent. Taken together, the TLR2 and TLR4 receptors are functional SAA receptors mediating MCP-1 release. Furthermore, the TLR2 and TLR4 are receptors for dysfunctional HDL. These results give a further inside in SAA as uremic toxin involved in uremia-related pro-inflammatory response in the vascular wall.
Highlights
Serum amyloid A (SAA) is a highly conserved acute-phase protein predominantly synthesized by the liver[1]
Once released into the blood circulation, the apolipoprotein SAA mainly incorporates into high-density lipoprotein (HDL), mainly HDL3, but it can be identified in low amounts in low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL)[1,11]
The results of this study demonstrate that unbound recombinant human SAA (rhSAA) and HDL-bound SAA activates pro-inflammatory acting TLR2 and TLR4 receptors in vascular cells and SAA exerts direct action on inflammatory conditions
Summary
Serum amyloid A (SAA) is a highly conserved acute-phase protein predominantly synthesized by the liver[1]. The precise physiological and pathophysiological role of SAA in acute and chronic inflammatory disorders is not known so far. It is well known that SAA plasma levels are elevated during septic conditions[2]. SAA plasma levels are significantly increased in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD)[6,7,8] where an independent correlation with the cardiovascular risk exists[8]. SAA-loaded HDL changes its composition during uremic condition resulting in a less anti-inflammatory capacity[12]. SAA incorporation is associated with disturbed metabolism[13,14] and decreased anti-inflammatory capacity of HDL especially from uremic patients[6,7]. Our results indicate that beside FPR2 activation[6] the TLR2 and TLR4 regulate the stimulation of MCP-1 production
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