The effect of myeloperoxidase-oxidized LDL on THP-1 macrophage polarization and repolarization

Abstract

Macrophages (Mφs) play a crucial role in the development of atherosclerosis by engulfing modified LDL particles and forming foam cells, the hallmark of atherosclerosis. Many studies suggest that myeloperoxidase-oxidized LDL (Mox-LDL) is an important pathophysiological model for LDL modification in vivo. Classically (M1) and alternatively activated (M2) Mφs are both implicated in the process of atherogenesis. Mφs are highly plastic cells whereby they undergo repolarization from M1 to M2 and vice versa. Since little is known about the effects of Mox-LDL on Mφ polarization and repolarization, our study aimed at evaluating the in vitro effects of Mox-LDL at this level through making use of the well-established model of human THP-1-derived Mφs. Resting M0-Mφs were polarized toward M1- and M2-Mφs, then M0-, M1- and M2-Mφs were all treated with physiological concentrations of Mox-LDL to assess the effect of Mox-LDL treatment on Mφ polarization and repolarization. Treatment of M0-Mφs with a physiological concentration of Mox-LDL had no significant effects at the level of their polarization. However, treatment of M1-Mφs with Mox-LDL resulted in a significant reduction in their IL-10 cytokine secretion. Our results point to a potential role of Mox-LDL in increasing the pro-inflammatory state in Mφs through reducing the release of the anti-inflammatory cytokine, IL-10.

Mechanisms of Oxidized LDL-Mediated Endothelial Dysfunction and Its Consequences for the Development of Atherosclerosis

“…MPO-oxidized LDL (Mox-LDL) is an important pathophysiological form for modified LDL in vivo . A very recent study has shown that Mox-LDL increases inflammation in macrophages through reducing the level of IL-10 (an anti-inflammatory cytokine) without affecting macrophage polarization ( 10 ). Elevated level of Mox-LDL will also potentially affect the functional status of endothelial cells and other types of vascular cells.…”

Role of myeloperoxidase in inflammation and atherosclerosis (Review)

“…Similarly, CD209 was significantly expressed in M2 macrophages when compared to the other subtypes. Although IL-6 release was minimal in all macrophage types except in the M1 macrophages where it was upregulated as expected, the same M1 macrophage subtype also showed a surprising and significant increase in IL-10 release ( 64 ). In our model, physiological concentrations of Mox-LDL had no significant effects on CD80/CD209 expression or IL-6/IL-10 release in Mox-LDL treated M0 macrophages ( 64 ).…”

“…Although IL-6 release was minimal in all macrophage types except in the M1 macrophages where it was upregulated as expected, the same M1 macrophage subtype also showed a surprising and significant increase in IL-10 release ( 64 ). In our model, physiological concentrations of Mox-LDL had no significant effects on CD80/CD209 expression or IL-6/IL-10 release in Mox-LDL treated M0 macrophages ( 64 ). However, treatment of THP-1 M1 macrophages with Mox-LDL had a significant negative effect on IL-10 cytokine secretion ( 64 ).…”

“…In our model, physiological concentrations of Mox-LDL had no significant effects on CD80/CD209 expression or IL-6/IL-10 release in Mox-LDL treated M0 macrophages ( 64 ). However, treatment of THP-1 M1 macrophages with Mox-LDL had a significant negative effect on IL-10 cytokine secretion ( 64 ). Overall, these results highlighted the inability of Mox-LDL to drive M0 macrophages towards an inflammatory or an alternative phenotype.…”

“…Nevertheless, these results are still insufficient and thus, should pave the way for ongoing research to further elucidate additional signaling pathways and novel functions of Mox-LDL; this would ultimately direct scientists towards a more complete understanding of the complex paradigm of ED in atherosclerosis. Moreover, regarding the effect of Mox-LDL on macrophage biology, we recently showed that Mox-LDL might play a potential role in the repolarization of THP-1 macrophages by increasing their pro-inflammatory state through the downregulation of the major anti-inflammatory cytokine IL-10( 64 ). Hopefully, these results will also lead the way to future investigations that will give the scientific community better insights into the immunomodulatory effects of Mox-LDL and the instrumental role that this particular form of modified LDL may play in the progression of atherosclerosis.…”