Macrophage Heterogeneity and Plasticity: Impact of Macrophage Biomarkers on Atherosclerosis

Table 1

Potential therapeutic targets in macrophage modulation.

Target/molecule	Study characteristics	Results	References
IL-10	Animal model: LDL receptor-deficient mice with IL-10 overexpression in T cells.	Monocyte/macrophage dysfunction, with reduced IFN-γ expression and foam cell apoptosis.	Pinderski et al. [15]
IL-13	Animal model: LDL receptor- and ApoE-knockout mice with atherosclerotic lesions that received exogenous IL-13.	LDLR−/− mice exhibited increased collagen synthesis and lower macrophage concentration in lesions. ApoE−/− mice showed decreased monocyte recruitment through VCAM-1, with possible alternative macrophage activation.	Cardilo-Reis et al. [16]
IL-19	Animal model: mice on atherogenic diets that received exogenous IL-19.	IL-19-treated mice showed lower amounts of macrophages, with Th2 polarization of circulating lymphocytes.	Johnson et al. [17]
IL-27	Animal model: mice deficient in IL-27 and IL-27 receptor.	Mice deficient in IL-27 and IL-27 receptor were more prone to atherosclerosis, with increased macrophage concentration in vascular walls, associated with higher oxLDL uptake and proinflammatory cytokine release.	Hirase et al. [18]
PPAR-γ	Animal model: mice without PPAR-γ in macrophages.	Mice without macrophagic PPAR-γ were more prone to obesity and insulin resistance; PPAR-γ activation appears necessary for alternative macrophage activation.	Odegaard et al. [19]
Statins	In vitro study: macrophages isolated from murine models were stimulated with IFN-γ, undergoing polarization towards M1 phenotype. These were exposed to varying doses of simvastatin in 9-hour cultures.	Exposure to simvastatin yielded an increase in IL-10 and CD206 expression and promoted M2 polarization.	Li et al. [20]
	Ex vivo study: carotid plaques from 140 patients were obtained, where 70 have preoperative statin use.	Those in the statin group showed lesser expression of TLR4 in macrophages and endothelial cells.	Katsargyris et al. [21]
LXR (Liver X Receptor)	Animal model: mice treated with LXR agonist T0901317.	Mice treated with T0901317 showed reduced macrophage infiltration and involution of plaques in early and late stages.	van der Stoep et al. [22]
Mhem induction	In vitro study: U937 cells (monocytic lineage) exposed to hemin (HO-1 activator) and IX Zinc Protoporphyrin.	Exposure to HO-1 inhibits expression of proinflammatory cytokines.	Ma et al. [23]
	In vitro study: macrophages from mice peritoneum and human atherosclerotic lesions.	The expression of HO-1 is a key in the acquisition of antioxidant activity in macrophages and is associated with decreased inflammation in the lesions.	Orozco et al. [24]
Metformin	In vitro study: endothelial cells from human coronary arteries, naïve and TRAF3IP2-deficient, exposed to HDL3, adiponectin, AICAR, and metformin.	Exposure to AMPK/Akt activators lowered production of superoxide, expression of TRAF3PI2, and oxLDL-C-mediated cell death.	Valente et al. [25]
	In vitro study: human monocyte-derived macrophages and mice bone marrow macrophages, exposed to heme and metformin.	Metformin induced activation of ATF1 at clinical concentrations (10 mol/L), with suppression of oxidative stress, enhanced cholesterol transport, prevention of foam cell formation, and suppression of macrophage activation.	Wan et al. [26]
	Ex vivo study: mononuclear cells from peripheral blood samples of healthy subjects, exposed to metformin, LPS, and Compound C (an AMPK inhibitor).	Monocyte-derived macrophages in the metformin group showed lower ROS production, with M2 polarization.	Bułdak et al. [27]
let-7c microRNA	In vitro study: M1 (GM-BMM) and M2 (M-BMM) macrophages derived from bone marrow of mice.	M2 macrophages showed higher let-7c mRNA levels. Their overexpression in M1 macrophages promoted shift towards M2 phenotype.	Banerjee et al. [28]
Modulation of NLRP3 inflammasomes	Animal model: ApoE knockout mice exposed to lentivirus.	Lentivirus silenced NLRP3, reducing plaque progression and local inflammation.	Zheng et al. [29]
	In vitro study: human macrophages treated with NLRP3 activators (ATP, cholesterol, serum amyloid A, and nigericin) and ethanol.	Ethanol attenuates macrophage activation and release of IL-1β.	Nurmi et al. [30]
	Clinical trial: 60 patients with coronary disease and 30 healthy subjects, randomly treated with atorvastatin or rosuvastatin. Expression of NLRP3 and IL-1β was assessed with reverse transcription-polymerase chain reaction.	Subjects treated with atorvastatin showed lower NLRP3 expression.	Satoh et al. [31]