Atherosclerosis (AS) is a slowly progressing chronic inflammatory disease of large arteries especially at sites of arterial branch points and bifurcations, which is characterized by the formation of atherosclerotic plaques. AS plaques are involved in an accumulation of lipids in arterial walls together with the infiltration of immunocytes. AS is initiated by alterations in cholesterol metabolism and, together with endothelial cell dysfunction, leads to the subendothelial retention of low-density lipoproteins (LDL). This vascular lipid deposition in turn alerts the immune system. These highly inflammatory AS lesions can grow slowly over years to eventually impede blood flow, which precipitates acute, occlusive lumenal thrombosis and its consequences: myocardial infarction ('heart attack'), unstable angina (accelerating chest pain due to ongoing heart muscle ischemia), sudden cardiac death, and stroke.

The Roles of Macrophages in AS

The key initiating step of AS is the subendothelial accumulation of lipoproteins to induce the activation of the overlying endothelium. Subsequently, monocytes are recruited to enter the subendothelial cell space and locate in the lesion site. Monocytes further differentiate into macrophages to actively scavenge normal and modified lipoproteins and become foam cells. Foam cells accumulate in the intima and go through apoptosis by cytokines. These foam cells persist in plaques to promote AS development. In these advanced plaques, macrophages continue to be major contributors to the inflammatory response. Dying macrophages release their lipid contents and tissue factors, which leads to forming a prothrombotic necrotic core triggering rupture and thrombosis finally.

Fig.1 Roles of macrophages in different stages of atherosclerosis progression. (Xu, 2019)

The Phenotypes and Functions of Macrophage in RA

In AS plaques, macrophages adapt their phenotype to different stimuli (Fig 2). The M1 macrophages are driven by interferon (IFNc) and Lipopolysaccharide (LPS), as well as by oxidized-LDL and cholesterol crystals; interleukin 4 (IL-4) induces the M2 macrophages; oxidized phospholipids (OxPL) drive monocytes toward a Mox phenotype; Mhems are induced by heme and M(Hb) are polarized by the hemoglobin/haptoglobin (Hb/Hp) complex and finally; C-X-C motif chemokine ligand 4 (CXCL4) drives the M4 phenotype. From a functional point of view, Mhem, M(Hb), and M2 macrophages prevent forming foam cells and play a crucial role in iron handling. M1 macrophages display a pro-inflammatory profile and are found in rupture-prone lesions which suggest that these macrophages are associated with plaque vulnerability. Mox macrophages exhibit reduced phagocytic capacity and express anti-oxidant genes. M4 macrophages also display reduced phagocytic capacity and a pro-inflammatory profile.

Fig.2 Macrophage subsets in the atherosclerotic lesion. (Xu, 2019)

Therapies of Targeting Macrophages in AS

• Reducing macrophage recruitment to atherosclerotic plaques by inhibition of chemokine receptors, such as chemokine (C-X3-C motif) receptor 1 (CX3CR1), chemokine receptor 2 (CCR2), and CCR5.
• Reprogramming of macrophages to an anti-inflammatory M2 phenotype.
• Maintaining levels of efferocytosis, such as reducing inflammation (in the case of IL-10 and liver X receptor (LXR) agonists) or promoting cholesterol efflux (in the case of LXR agonists, increasing autophagy or ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette, sub-family G member 1 (ABCG1) expression levels by inhibiting the miR-33).
• Novel drug delivery systems selectively modify macrophages including inducing cell apoptosis, inhibiting cell proliferation, and introducing anti-inflammatory agents.

The discovery of different macrophage phenotypes provides an opportunity to study the relationship between macrophage phenotypes and diseases. Based on a Macrophage Therapeutics Development Platform, Creative Biolabs is offering the most comprehensive services for macrophage development projects. We are committed to providing customized professional and efficient solutions to support your projects.

Our Featured Services Including but Not Limited to:

• Macrophage Isolation and Culture Service
• Macrophage Polarization Assay
• Macrophage Polarization Phenotype Identification Service
• Macrophage Characterization Service
• Macrophage Reprogramming Service
• Macrophage Engineering Service for Drug Delivery
• Macrophage Marker Development Service

Please contact us directly for more specific solutions.

Reference

1. Xu, H.; et al. Vascular macrophages in Atherosclerosis. Journal of Immunology Research. 2019, 2019(4):1-14.