Alternative macrophages in atherosclerosis: not always protective!

Abstract

Atherosclerosis is a chronic inflammatory disease of the vasculature that is initiated by cholesterol deposition into the arterial wall, which triggers the infiltration of immune and inflammatory cells, including monocytes and macrophages. As atherosclerotic plaques progress, localized hypoxia promotes compensatory angiogenesis from the vasa vasorum. Immature neovessels are prone to leakage, thus destabilizing the plaque and leading to intraplaque hemorrhage. Macrophages with different phenotypes, ranging from classical inflammatory subtypes to alternatively activated antiinflammatory macrophages, have been identified in atherosclerotic lesions. Antiinflammatory hemoglobin-scavenging CD163+ macrophages are present in neovessel- and hemorrhage-rich areas; however, the role of these macrophages in atherogenesis has been unclear. In this issue of the JCI, Guo, Akahori, and colleagues show that CD163+ macrophages promote angiogenesis, vessel permeability, and leucocyte infiltration in human and mouse atherosclerotic lesions through a mechanism involving hemoglobin:haptoglobin/CD163/HIF1α-mediated VEGF induction. This study thus identifies proatherogenic properties of CD163+ macrophages, which previously were thought to be beneficial.

Figure 1. Alternative CD163⁺ macrophages associate with atherosclerotic plaque hemorrhage and leakage.

CD163⁺ M(Hb) macrophages are abundant in hemorrhage areas, in which erythrolysis provides high amounts of Hb (i). In complex with Hp, Hb is scavenged by CD163 and induces the expression of FPN, which promotes intracellular Fe²⁺ depletion (i). Ferrous iron efflux leads to decreased prolyl hydroxylase 2 (PHD2) activity and subsequent stabilization of HIF1α, which enhances VEGF expression (i) and intraplaque neovascularization. VEGF promotes VEGFR2-dependent VE-cadherin internalization (ii) and neovessel leakage (ii). VEGF also enhances VCAM expression and macrophage infiltration (iii), therby increasing plaque progression and erosion. ECs, endothelial cells; SMCs, smooth muscle cells.