Cytokines associated with immune response in atherosclerosis

Abstract

Inflammation is an essential mechanism of immune response that involves a large number of different immune cells. Atherosclerosis is essentially an inflammatory disease caused by inappropriate activities of immune cells. During this process, various cytokines activate immune cells, regulate and transmit immune cell signals, and stimulate a local inflammatory environment. In this study, we reviewed the cytokines associated with immune activity in atherosclerosis, including their roles in immune cell activation and mediating immune cell chemotaxis. The findings give important insights into inflammatory immune microenvironment, including basic mechanisms and interactions, providing new ideas and options for clinical detection and treatment of this disease.

Keywords: Atherosclerosis; cytokine; immunity.

Figure 1

Schematic overview of cytokines involved in immune cell activation during atherosclerosis. Cytokines can be expressed in almost all types of cells in this environment, especially macrophages. Some of them, like TNF-α and IFN-γ, act as critical roles in this network, promoting the expression of other cytokines including IL-6, IL-8, CCL2, CXCL16, etc. IL-18 drives T cell polarization and induces MMP expression in vascular smooth muscle cells. IL-23 is mainly expressed by macrophages, causing subsequent inflammatory factors reaction. IL-1β has multiple pro-inflammatory functions, other than inducing MMPs and other cytokines, it can also affect the proliferation and migration of vascular smooth muscle cells. IL-6, also known as a key cytokine with diverse functions, can promote low-density lipoprotein uptake in macrophages and stimulate endothelial cells to secret adhesion molecules. More details are offered in the text. IL: interleukin; IFN-γ: interferon-γ; CCL2: C-C motif chemokine ligand 2; CXCL16: C-X-C motif chemokine ligand 16; MIP-1α: macrophage inflammatory protein-1α; CAMs: cell adhesion molecules; LPS: lipopolysaccharide; TMAO: trimetlylamine oxide; TNF-α: tumor necrosis factor-α; MMPs: matrix metalloproteinases. Figure was created using BioRender.com.

Figure 2

Schematic overview of cytokines mediating immune cell chemotaxis during atherosclerosis. CCL2 can attract monocytes to the lesion and drive them to differentiate into macrophages. CCL2 further promotes macrophages polarization to M1. CX3CL1 was released by apoptotic cells and then recruits macrophages to form foam cells. MIF is a multipotent atypical chemokine, it selectively recruits T cells, monocytes and leucocytes through different receptors. It also promotes the expression of other cytokines, VCAM-1 and ICAM-1. Platelets are the factory of several chemokines including CCL5, CXCL4 and CXCL16. CCL5 can stop leucocytes from moving through the CCR1 and CCR5 receptors and migrate leucocytes to the endothelium. CXCL4 can also bind to CCR1 and form a complex with CCL5, performing chemotaxis. CXCL16 promotes oxLDL uptake of macrophages other than its chemotactic function. CXCL12 exerts diverse effects including recruitment and promoting adhesion by binding to different receptors. More details are offered in the text. CCL2: C-C motif chemokine ligand 2; CCL5: C-C motif chemokine ligand 5; CCR1: C-C motif chemokine receptor 1; CCR2: C-C motif chemokine receptor 2; CCR5: C-C Motif Chemokine Receptor 5; CXCL4: C-X-C motif chemokine ligand 4; CXCL12: C-X-C motif chemokine ligand 12; CXCL16: C-X-C motif chemokine ligand 16; CXCR2: C-X-C motif chemokine receptor 2; CXCR6: C-X-C motif chemokine receptor 6; CXCR7: C-X-C motif chemokine receptor 7; CX3CL1: C-X3-C motif chemokine ligand 1; CX3CR1: C-X3-C motif chemokine receptor 1; TNF-α: tumor necrosis factor-α; IL: interleukin; MIF: macrophage migration inhibitory factor; iNOS: inducible nitric oxide synthase; NO: nitric oxide; LDL: low-density lipoprotein; oxLDL: oxidized low-density lipoprotein. Figure was created using BioRender.com.