Abstract
Background:
Atherosclerosis (AS) is a cardiovascular problem, which is featured by the accumulation of lipids in the intimal layer of the arterial wall and inflammatory reaction of immune cells. CCL17 is an inflammatory mediator associated with promoting AS. Nevertheless, the specific role of CCL17 and its upstream regulatory mechanisms in macrophage mediated inflammation and AS remain unclear.
Methods:
An AS mice model was established by subjecting ApoE-/- mice to a high-fat diet (HFD). Constructing an AS cell model by treating primary macrophages with oxidized low-density lipoprotein (ox LDL). Injecting shRNA wrapped by AAV virus into the tail vein of mice knocked down CCL17 and SENP3 in mice. Hematoxylin-eosin (HE) and oil red O staining were used to detect arterial injury in mice. The changes of Treg cells were detected by flow sorting. Cycloheximide (CHX) and immunoprecipitation were used to detect the level of DeSUMOylation of CCL17 modified by SENP3.
Results:
The CCL17 and SENP3 expression in plaque sample of AS mice were significantly up-regulated. Knocking down CCL17 or SENP3 in mice could reverse the vascular damage, lipid accumulation, the increase of the blood lipid levels and the increase of inflammatory reaction in AS mice. On the molecular mechanism level, SENP3 increased the protein stability of CCL17 and thus increased CCL17 expression by DeSUMOylation modification at K115 site of CCL17 protein. In macrophages induced by oxLDL, CCL17 and CCL22 affect the chemotaxis of Treg competitively.
Conclusion:
This study showed that SENP3 mediated deSUMOylation of CCL17, increase CCL17 expression in macrophage. CCL17 secreted by macrophage regulating Treg recruitment through the competitive interaction between CCL17 and CCL22 and thus aggravated AS. Our findings provide a new regulatory mechanism and potential target for AS treatment.