High‐density lipoprotein inhibits human M1 macrophage polarization through redistribution of caveolin‐1

Abstract

BACKGROUND AND PURPOSEMonocyte-derived macrophages are critical in the development of atherosclerosis and can adopt a wide range of functional phenotypes depending on their surrounding milieu. High-density lipoproteins (HDLs) have many cardio-protective properties including potent anti-inflammatory effects. We investigated the effects of HDL on human macrophage phenotype and the mechanisms by which these occur. EXPERIMENTAL APPROACHHuman blood monocytes were differentiated into macrophages in the presence or absence of HDL and were then induced to either an inflammatory macrophage (M1) or anti-inflammatory macrophage (M2) phenotype using LPS and IFN-γ or IL-4, respectively. KEY RESULTSHDL inhibited the induction of macrophages to an M1-phenotype, as evidenced by a decrease in the expression of M1-specific cell surface markers CD192 and CD64, as well as M1-associated inflammatory genes TNF-α, IL-6 and MCP-1 (CCL2). HDL also inhibited M1 function by reducing the production of ROS. In contrast, HDL had no effect on macrophage induction to the M2-phenotype. Similarly, methyl-β-cyclodextrin, a non-specific cholesterol acceptor also suppressed the induction of M1 suggesting that cholesterol efflux is important in this process. Furthermore, HDL decreased membrane caveolin-1 in M1 macrophages. We confirmed that caveolin-1 is required for HDL to inhibit M1 induction as bone marrow-derived macrophages from caveolin-1 knockout mice continued to polarize into M1-phenotype despite the presence of HDL. Moreover, HDL decreased ERK1/2 and STAT3 phosphorylation in M1 macrophages. CONCLUSIONS AND IMPLICATIONSWe concluded that HDL reduces the induction of macrophages to the inflammatory M1-phenotype via redistribution of caveolin-1, preventing the activation of ERK1/2 and STAT3. LINKED ARTICLES

ANG II facilitated CD11+Ly6Chi cells reprogramming into M1-like macrophage through Erk1/2 or p38-Stat3 pathway and involved in EAM

“…And our data also were in line with published reports that most actions of ANG II were primarily carried out by AT 1 R signaling . Additionally, inhibition of Erk1/2, p38, or Stat3 could also obviously ameliorate the cardiac injury, which cannot completely owe to prevent M1 polarization; as all these inhibitors are not specific for macrophage polarization, more and more data indicated that macrophage polarization was associated with Erk1/2, p38, or Stat3; therefore, our data suggested that to prevent the macrophage polarization, the EAM development could be ameliorated.…”

Scavenging dicarbonyls with 5’-O-pentyl-pyridoxamine increases HDL net cholesterol efflux capacity and attenuates atherosclerosis and insulin resistance

“…Studies have shown that HDL abrogates the induction of macrophages to an M1phenotype, as demonstrated by a reduction in the cell surface markers CD192 and CD64, as well as by decreased expression of MCP-1 (CCL2) [52]. HDL inhibits ERK1/2 and STAT3 phosphorylation in M1 macrophages [52]. HDL also increases expression of the M2 markers Arg1 and Fizz-1 via a mechanism requiring STAT6 [53].…”

Micro‐environment and intracellular metabolism modulation of adipose tissue macrophage polarization in relation to chronic inflammatory diseases

“…63 HDL also inhibits the phenotype and function of M1 by decreasing the M1-specific markers and inflammatory genes TNF-α, IL-6, and MCP-1 via redistribution of membrane caveolin-1 and phosphorylation of ERK1/2 in human macrophages. 64 However, HDLmediated cholesterol efflux was impaired under the obese state in humans, 65 which was related to elevated monocytes, indicating a pro-inflammatory state in these subjects. 66 A recent study that reported the proteomic composition of HDL, but not the efflux capacity, reflects the differential mediation effects of reverse cholesterol transportation by saturated and monounsaturated fat diets in mice.…”

“…Promoting intracellular cholesterol efflux by increasing HDL in macrophages has been found to induce the polarization of macrophages to the M2 phenotype, thus improving inflammation, oxidative damage, and AS in apoE knockout mice . HDL also inhibits the phenotype and function of M1 by decreasing the M1‐specific markers and inflammatory genes TNF‐α, IL‐6, and MCP‐1 via redistribution of membrane caveolin‐1 and phosphorylation of ERK1/2 in human macrophages . However, HDL‐mediated cholesterol efflux was impaired under the obese state in humans, which was related to elevated monocytes, indicating a pro‐inflammatory state in these subjects .…”