Role of the CCL2-CCR2 axis in cardiovascular disease: Pathogenesis and clinical implications

Abstract

The CCL2-CCR2 axis is one of the major chemokine signaling pathways that has received special attention because of its function in the development and progression of cardiovascular disease. Numerous investigations have been performed over the past decades to explore the function of the CCL2-CCR2 signaling axis in cardiovascular disease. Laboratory data on the CCL2-CCR2 axis for cardiovascular disease have shown satisfactory outcomes, yet its clinical translation remains challenging. In this article, we describe the mechanisms of action of the CCL2-CCR2 axis in the development and evolution of cardiovascular diseases including heart failure, atherosclerosis and coronary atherosclerotic heart disease, hypertension and myocardial disease. Laboratory and clinical data on the use of the CCL2-CCR2 pathway as a targeted therapy for cardiovascular diseases are summarized. The potential of the CCL2-CCR2 axis in the treatment of cardiovascular diseases is explored.

Keywords: CCL2; CCR2; cardiovascular disease; chemokine; inflammation.

Figure 1

CCL2-CCR2 network and expression in human tissues. (A) Chemokines and their receptor networks associated with the CCL2-CCR2 axis (9). The chemokine family is a huge system of ligands and GPCRS. In this network, CCL2 can bind to a variety of receptors, including the classical chemokine receptors (shaded in pink) CCR1, CCR2, CCR4 and the atypical chemokine receptors (shaded in gray) ACKR1, ACKR2. CCR2 can also bind to a variety of ligands (in red), including CCL2, CCL7, CCL8, CCL11, CCL13, CCL16, CCL26. (B) CCL2 and CCR2 RNA expression in human tissues, X-axis represents the consensus data based on normalized expression (nTPM) values (data from https://www.proteinatlas.org).

Figure 2

Schematic diagram of the CCL2-CCR2 axis and its signaling pathway. CCR2 is a G PCR. Upon binding of CCR2 to CCL2, a range of signaling downstream is activated, for instance, the JAK/STAT pathway, MAPK pathway and PI3K/Akt pathway. A variety of transcription factors and genes are then activated to participate in cytokine production, cell growth and differentiation, cell survival, migration and apoptosis.This figure was created with BioRender.com.

Figure 3

Role of the CCL2-CCR2 axis in cardiovascular disease. The CCL2-CCR2 axis fosters monocyte mobilization from the bone marrow and recruits circulating monocytes to the site of the lesion. In plaques, monocytes are differentiated to macrophages, which proliferate, become foam cells, and coordinate the inflammatory response (A). In infarcted myocardial tissue, monocytes are recruited and differentiated into macrophages that influence MI disease progression (B). In hypertension, monocytes infiltrate into the vascular adventitia, perivascular fat, heart, kidney, and brain, and are involved in elevated blood pressure and end-organ damage (C). In cardiomyopathies (dilated cardiomyopathy as an example), monocytes infiltrate and differentiate into macrophages in the damaged myocardium and participate in the development and progression of cardiomyopathies (D). This figure was created with BioRender.com.