Mechanisms that regulate macrophage burden in atherosclerosis

Abstract

Mononuclear phagocytes (MPs) relevant to atherosclerosis include monocytes, macrophages, and dendritic cells. A decade ago, studies on macrophage behavior in atherosclerotic lesions were often limited to quantification of total macrophage area in cross-sections of plaques. Although technological advances are still needed to examine plaque MP populations in an increasingly dynamic and informative manner, innovative methods to interrogate the biology of MPs in atherosclerotic plaques developed in the past few years point to several mechanisms that regulate the accumulation and function of MPs within plaques. Here, I review the evolution of atherosclerotic plaques with respect to changes in the MP compartment from the initiation of plaque to its progression and regression, discussing the roles that recruitment, proliferation, and retention of MPs play at these different disease stages. Additional work in the future will be needed to better distinguish macrophages and dendritic cells in plaque and to address some basic unknowns in the field, including just how cholesterol drives accumulation of macrophages in lesions to build plaques in the first place and how macrophages as major effectors of innate immunity work together with components of the adaptive immune response to drive atherosclerosis. Answers to these questions are sought with the goal in mind of reversing disease where it exists and preventing its development where it does not.

Keywords: atherosclerosis; macrophages; monocytes.

Fig. 1

Proposed signalling pathways in macrophages that link cholesterol to their accumulation in atherosclerotic plaques. Two major drivers of increased macrophage accumulation in plaques are proliferation (left) and recruitment (right). The quantitative importance of macrophage proliferation in overall macrophage accumulation has only recently been appreciated so remains understudied. So far, only signaling from SR-A has been associated with proliferation. Signals proposed to regulate macrophage accumulation are many (right) and include binding of oxidized LDL to TLRs that in turn activate NFκB. Transporters like ABCA1 at the plasma membrane may control the assembly of signaling molecules through regulation of membrane cholesterol. The inflammasome, coupled with TLR activation, generates IL-1β and free fatty acid signaling triggers IL-1α production in an inflammasome-independent manner. Signalling through IFNγ receptor activates STAT-1 that in turn influences the expression of genes including chemokines like CXLC10 and CCL5 and adhesion molecules like ICAM-1. IL-1α and IL-1β are classic proinflammatory cytokines that target the endothelium to promote, for instance, recruitment of monocytes.