Macrophage Differentiation and Function in Atherosclerosis: Opportunities for Therapeutic Intervention?

Abstract

The macrophage is exquisitely sensitive to its microenvironment, as demonstrated primarily through in vitro study. Changes in macrophage phenotype and function within the atherosclerotic plaque have profound consequences for plaque biology, including rupture and arterial thrombosis leading to clinical events such as myocardial infarction. We review the evidence for dynamic changes in macrophage numbers and macrophage differentiation within the atherosclerotic plaque microenvironment and discuss potential approaches to target macrophage differentiation for therapeutic benefit in cardiovascular disease.

Plaque-hyaluronidase-responsive high-density-lipoprotein-mimetic nanoparticles for multistage intimal-macrophage-targeted drug delivery and enhanced anti-atherosclerotic therapy

“…3,46,47 Despite the inherent atheroprotective properties of rHDL offering superiority over other vehicles for anti-atherogenic therapy, the insufficient specificity of conventional s-rHDL for iMΦ and the fact that s-rHDL shows limited cholesterol efflux ability remain challenging issues. These challenges motivated our present research to engineer a novel type of HDL-based nanovector delivering agents into iMΦ more efficiently, as well as promoting cholesterol removal from iMΦ.…”

Are oxidised low-density lipoproteins the true inducers of inflammation in atherosclerosis?

“…Later, these housekeepers are gradually substituted by M1-like inflammatory macrophages derived from newly recruited inflammatory monocytes, but also from resident M2-like macrophages that switch towards M1 polarisation. In time, the complication of atheromas is dependent on the balance between the expression of pro-and antiinflammatory programs by macrophages in the lesions [6,32,76,114,[120][121][122]. All these proposals concur with the thesis that the accumulated ox-LDL is not proinflammatory, but that instead they are a non-dangerous oxidative waste that polarises macrophages towards a M2-like phenotype.…”

“…It is well known that the release of IFN-g makes atheromas vulnerable and prone to rupture [32]. This cytokine is produced by Th1, NK and iNKT cells in response to antigens and/or a cytokine profile released by inflammatory macrophages (M1).…”

A Novel Role of Matrix Metalloproteinase-8 in Macrophage Differentiation and Polarization

“…The bone marrow was triturated using an 18-gauge needle and passed through a 70-m nylon mesh cell strainer (Becton Dickinson, Franklin Lakes, NJ) to make a single cell suspension in Roswell Park Memorial Institute (RPMI)-1640 supplemented with 2% serum, 10 mM Hepes. Red blood cells in bone marrow cells were lysed with a lysis buffer (8.3 g of NH 4 Cl, 1.0 g of KHCO 3 , and 1.8 ml of 5% EDTA in 1000 ml). Bone marrow mononuclear cells were washed three times and cultured in the RPMI-1640 supplemented with 10% serum and 5 ng/ml of M-CSF for 7-14 days to induce BMM differentiation and maturation.…”

“…Lipopolysaccharides, interleukin-1␤ (IL-1␤), and cytokines secreted by Th1 lymphocytes, such as interferon-␥ (IFN-␥), induce a "classic" M phenotype (M1), whereas Th2 lymphocyte cytokines, such as IL-4 and IL-13, promote an "alternative" M phenotype (M2) (1)(2)(3)(4)(5)(6)(7). Activated M1-M produce proinflammatory cytokines such as tumor necrosis factor-␣ (TNF-␣), IL-6, and IL-12, whereas M2-M dampen the inflammatory state by producing anti-inflammatory molecules, such as IL-10, IL-1 receptor antagonist, and transforming growth factor (TGF)-␤.…”