Statins Directly Influence the Polarization of Adipose Tissue Macrophages: A Role in Chronic Inflammation

Abstract

Statins represent one of the most widely used classes of drugs in current medicine. In addition to a substantial decrease in atherogenic low density lipoprotein (LDL) particle concentrations, several large trials have documented their potent anti-inflammatory activity. Based on our preliminary data, we showed that statins are able to decrease the proportion of pro-inflammatory macrophages (CD14 + 16 + CD36high) in visceral adipose tissue in humans. In the present study including 118 healthy individuals (living kidney donors), a very close relationship between the pro-inflammatory macrophage proportion and LDL cholesterol levels was found. This was confirmed after adjustment for the most important risk factors. The effect of statins on the proportion of pro-inflammatory macrophages was also confirmed in an experimental model of the Prague hereditary hypercholesterolemia rat. A direct anti-inflammatory effect of fluvastatin on human macrophage polarization in vitro was documented. Based on modifying the LDL cholesterol concentrations, statins are suggested to decrease the cholesterol inflow through the lipid raft of macrophages in adipose tissue and hypercholesterolemia to enhance the pro-inflammatory macrophage phenotype polarization. On the contrary, due to their opposite effect, statins respond with anti-inflammatory activity, affecting the whole organism.

The Immunomodulatory Effects of Statins on Macrophages

“…Similarly, rosuvastatin-loaded nanomicelles were found to stimulate microglia/macrophages to an M2 phenotype in a mouse model of intracerebral haemorrhage, where they also reported reduced tissue levels of IL-1β and TNFα and increased levels of IL-10 [165]. Various other studies in a range of rodent models have also reported atorvastatin and pravastatin to have macrophage-polarizing actions, demonstrated by augmented M1/M2 ratios [103,[166][167][168]. Numerous reports have also demonstrated statin treatment to decrease macrophage infiltration and proliferation within inflamed tissues [95,167,[169][170][171][172], which are features associated with atherosclerotic lesion regression [173].…”

“…In opposition to this, John et al found no significant difference in patients treated with simvastatin [182]. Finally, a recent study by Kauerova et al investigating the influence of statin treatment on macrophage polarization in human adipose tissue reported statin therapy to increase the proportion of M2-like macrophages compared to M1-like ones [103]. Similarly, to the in vivo reports, researchers were unable to elucidate the underlying mechanisms of these effects.…”

“…[94] Human PBMC derived macrophages Decreased the activity of iNOS in M1 macrophages. [103] Table 2. Cont.…”

“…The upregulated gene and protein expression of Krüppel-like factor 2 [121] (a potent regulator of pro-inflammatory activation) and SOD1 [114] (associated with increased antioxidant enzyme activity and decreased ROS production [143]) have also been reported to occur in statin-treated macrophages and may contribute to the suppression of NF-κB-driven signalling pathways. Statin-mediated inhibition of the IκB/NF-κB pathway has been shown to result in a global anti-inflammatory effect on macrophages, with mRNA and protein analysis revealing the attenuated expression of many pro-inflammatory associated mediators, including cytokines (TNFα, IL-1β, and IL-6) [104,121], chemokines (MCP-1 and MIP-1α/β) [121], and tissue factor (a membrane-bound glycoprotein that plays a prominent role in the extrinsic pathway of blood coagulation and fibrin deposition) [98], and NO production [81,103,104]. Importantly, the inhibitory effects of statin treatment on NF-κB-induced cytokine synthesis have also been seen when using the CVD-relevant endogenous ligand oxLDL and are associated with reduced macrophage oxLDL loading and foam cell formation [84,114,116,117].…”

Macrophages in Health and Non-Infectious Disease

“…Kauerova with coauthors [ 8 ] investigated the influence of statins on macrophage polarization in a larger number of individuals than they did in their previous study. They analyzed data of two studies with the addition of an animal model, and the model of human macrophages to study the effect of statin in vitro.…”