Statins and Bempedoic Acid: Different Actions of Cholesterol Inhibitors on Macrophage Activation

Abstract

Statins represent the most prescribed class of drugs for the treatment of hypercholesterolemia. Effects that go beyond lipid-lowering actions have been suggested to contribute to their beneficial pharmacological properties. Whether and how statins act on macrophages has been a matter of debate. In the present study, we aimed at characterizing the impact of statins on macrophage polarization and comparing these to the effects of bempedoic acid, a recently registered drug for the treatment of hypercholesterolemia, which has been suggested to have a similar beneficial profile but fewer side effects. Treatment of primary murine macrophages with two different statins, i.e., simvastatin and cerivastatin, impaired phagocytotic activity and, concurrently, enhanced pro-inflammatory responses upon short-term lipopolysaccharide challenge, as characterized by an induction of tumor necrosis factor (TNF), interleukin (IL) 1β, and IL6. In contrast, no differences were observed under long-term inflammatory (M1) or anti-inflammatory (M2) conditions, and neither inducible NO synthase (iNOS) expression nor nitric oxide production was altered. Statin treatment led to extracellular-signal regulated kinase (ERK) activation, and the pro-inflammatory statin effects were abolished by ERK inhibition. Bempedoic acid only had a negligible impact on macrophage responses when compared with statins. Taken together, our data point toward an immunomodulatory effect of statins on macrophage polarization, which is absent upon bempedoic acid treatment.

The Immunomodulatory Effects of Statins on Macrophages

“…Moreover, in agreement with anti-inflammatory reports, they noted a decreased surface expression of MHC-II. Another study by Linnenberger et al agreed with this finding that statin treatment had no effect on macrophage stimulation by IFN-γ (despite enhancing LPS-induced expression of TNF, IL-1β, and IL-6) [97].…”

“…Specifically, statin treatment decreased c-FOS binding to the AP-1 promoter region (a negative regulator of the signalling system) whilst simultaneously enhancing JNK-mediated c-Jun phosphorylation, thereby stimulating the transcription of inflammatory genes. In keeping with this, atorvastatin and simvastatin pre-treatment is observed to enhance TLR2/TLR4 ligand-stimulated IL-6 and TNFα production [82], and various research groups have found statins to induce the activation of the MyD88 pathway transcription factor NF-κB [92,97]…”

“…It is worth noting that even when taking all these factors into consideration, some investigations have found that statins simultaneously promote pro-and anti-inflammatory phenotypes [92,97,110,122]. One example of this is a study by Linnenberger et al in which, under both unstimulated and LPS-activated conditions, statins enhanced M1-like proinflammatory cytokine release but also increased the expression of arginase, a classical marker of M2 macrophages which antagonises NO production (indeed, NO release was unaltered upon statin treatment).…”

Characterization of Anti-Cancer Activities of Violacein: Actions on Tumor Cells and the Tumor Microenvironment

“…BMMs were obtained from wildtype or Nlrp3 knockout C57B/6 mice and cultivated as described previously ( 27 ). Cells were seeded per well into 96 well plates (75,000 per well) for MTT assays and into 12 well plates (500,000 per well) for RT-qPCR.…”

Macrophage Polarization: Learning to Manage It

“…The paper of Linnenberger and colleagues compared the pro-and anti-inflammatory effects of statins with bempedoic acid (BA), recently registered as a drug for the treatment of hypercholesterolemia. They concluded that BA is effective in the rescue of the phagocytic activity of macrophages differently from statins, and does not induce side effects as statins do [10] (Figure 2F). Modulation of macrophage phenotypes has been suggested as a novel strategy for the treatment of inflammatory pathologies.…”