Circulating pathogen associated molecular pattern - Binding proteins and High Mobility Group Box protein 1 in nascent metabolic syndrome: Implications for cellular Toll-like receptor activity

- This study was aimed at elucidating the roles of monocytes and adipose tissue as cellular sources of Inflammation in nascent Metabolic Syndrome, uncomplicated by diabetes or CVD.
- In this paper, we make a novel observation that in patients with nascent MetS, soluble CD14 compared to LBP provides a better measure of increased TLR4 activity and cellular inflammation.
- We also show in-vitro that soluble CD14 is superior to LBP in activating TLR4 activity in human aortic endothelial cells.
- This could have implications to the increased CVD risk of MetS.
- Furthermore we make the additional novel observation, that the DAMP, HMGB1 also captures cellular inflammation although not specific for TLR activity in MetS.

ObjectiveThe Metabolic Syndrome, (MetS) a global epidemic, is a state of low grade chronic inflammation and confers an increased risk for diabetes and CVD. We have previously reported increased activity of the pathogen recognition receptors, Toll-like receptors (TLRs), TLR2 and TLR4 in MetS. We hypothesized that increased TLR activity in MetS is due in part to increased levels of circulating PAMP-binding proteins, soluble CD14 (sCD14), lipopolysaccharide binding protein (LBP) and the damage associated molecular pattern (DAMP), High Mobility Group Box protein 1 (HMGB-1).MethodsWe measured sCD14, LBP and HMGB-1 in fasting plasma from nascent MetS (n = 37) and healthy control subjects (n = 32) by ELISA. We also investigated the effects of sCD14 and LBP on TLR4 activity in human aortic endothelial cells (HAECs).ResultsFollowing adjustment for body mass index and waist circumference, sCD14, LBP and HMGB-1 levels remained significantly increased in MetS. Also their levels increased with increasing numbers of MetS risk factors. Only sCD14 correlated significantly with monocyte TLR4 protein and activity. None of these soluble biomarkers correlated with TLR2 protein. Both sCD14 and HMGB-1 correlated significantly with HOMA-IR.In LPS primed HAECs, sCD14 compared to LBP, resulted in a greater increase in both TLR4 abundance and inflammatory biomediators (NF-κB, IL-1β, IL-8 and TNF-α).ConclusionThus, we make the novel observation that sCD14 reflects increased monocyte TLR4 protein and activity in nascent MetS and by contributing to increased cellular inflammation could explain, in part, the increased risk for diabetes and CVD.