CCL19 and CCL21 modulate the inflammatory milieu in atherosclerotic lesions

Abstract

Despite advances in the pharmacologic and interventional treatment of coronary artery disease, atherosclerosis remains the leading cause of death worldwide. Atherosclerosis is a chronic inflammatory disease, and elevated expression of CCL19 and CCL21 has been observed in ruptured lesions of coronary arteries of patients with myocardial infarction and carotid plaques of patients with ischemic symptoms, as well as in plasma of coronary artery disease patients. However, the exact role of CCL19 and CCL21 in atherosclerosis remains unknown. In order to identify CCL19 and CCL21 as a novel therapeutic target, we performed bone marrow transplantation as an immunomodulatory treatment concept. Bone marrow of plt/plt mice (lacking CCL19 and CCL21-Ser) was transplanted into atherogenic Ldlr−/− mice. The study demonstrated a significantly increased inflammatory cellular infiltration into the lesions of plt/plt/Ldlr−/− mice versus controls. Although the level of chemoattraction was increased, messenger ribonucleic acid and protein levels in thoracic aorta and serum of several proinflammatory cytokines (TNFα, IFNγ, IL-6, IL-12, and IL-17) were significantly reduced in plt/plt/Ldlr−/− versus control mice. Increased influx, accompanied by reduced activation of leukocytes in atherosclerotic lesion, was accompanied by increased plaque stability but unchanged lesion development. In conclusion, modulation of the chemokines CCL19 and CCL21 represents a potent immunoregulatory treatment approach, and thus represents a novel therapeutic target to stabilize atherosclerotic lesions.

Shrunken Pore Syndrome Is Associated With Increased Levels of Atherosclerosis-Promoting Proteins

“…As can be seen from the present proteomic studies, a large proportion of the changes in plasma levels of proteins in SPS or reduced GFR concerns proteins with signaling functions. A survey of the literature suggests that of the 30 changes specific for SPS, 18 promote, or are associated with, atherosclerosis38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 (Table 2). The same is true for 12 of the 31 changes occurring in patients with both SPS and reduced GFR60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 and for 10 of the 27 changes specific for reduced mGFR72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84 (Table 2).…”

Inflammation: A Novel Therapeutic Target/Direction in Atherosclerosis

“…Until now, there is no information about a small molecule or another modulator that is directly targeted at CCL17. However, research results of virtual ligand screening research about small-molecule inhibitors of the CCL17–CCL4 interaction suggest that validation of CCL17 as a target to inhibit atherogenesis is feasible [160, 161].…”

“…In humans, the increased level of CCL19 and CCL21 is correlated with atherosclerotic carotid plaques [161]. The modulation of CCL19 and CCL21 chemokines in LDLr –/– mice model reduced the level of pro-inflammatory cytokines, such as IL-12 and IFN-γ, which resulted in atherosclerotic plaque stabilization [161, 163].…”

Gene and Protein Expression of Chemokine (C-C-Motif) Ligand 19 is Upregulated in Unstable Carotid Atherosclerotic Plaques

“…A previous study has shown a possible link between CCL19 and plaque destabilisation through recruitment of T cells and macrophages. 39 In a recent atherogenic mouse model study, 40 it was found that CCL19 had a significant role in cellular activation, especially of macrophages in atherosclerotic lesions. It was also noted that CCL19 influences the activation of leukocytes, lipid uptake of macrophages, and foam cell formation within atherosclerotic plaques.…”