IL-37 Expression in Patients with Abdominal Aortic Aneurysm and Its Role in the Necroptosis of Vascular Smooth Muscle Cells

Abstract

Background. Our previous studies have shown that interleukin- (IL-) 37 plays a protective role in patients and animal models with coronary artery disease. However, the role of IL-37 in patients with abdominal aortic aneurysm (AAA), another artery disease, is yet to be elucidated. Methods and Results. AAA tissues and plasma samples were obtained from patients with or without surgical intervention. Normal renal aortic tissues were collected from kidney transplant donors. Our findings established that in AAA, IL-37 was distributed in endothelial cells, macrophages, and vascular smooth muscle cells (VSMCs) and that it was chiefly concentrated in VSMCs. Furthermore, the expression was found to be downregulated compared with that in normal artery tissues. Immunofluorescence showed that, unlike normal arteries, IL-37 was translocated to the nucleus of VSMCs in AAA. Moreover, in patients with AAA, the expressions of IL-37, IL-6, and tumor necrosis factor- (TNF-) α were increased in the plasma in comparison with the healthy controls. Correlation analysis revealed that IL-37 was positively correlated with IL-6, TNF-α, age, aneurysm diameter, and blood pressure. Furthermore, human aortic vascular smooth muscle cells (HASMCs) were stimulated with angiotensin II (AngII) in vitro to simulate smooth muscle cell (SMC) damage in AAA. A decrease in IL-37 expression and an increase in receptor-interacting serine/threonine-protein kinase 3 (RIPK3) expression were observed in HASMCs stimulated with AngII. On this basis, inhibition of RIPK3 with GSK’872 significantly attenuated necroptosis. Moreover, the necroptosis rates were significantly lowered in HASMCs treated with recombinant IL-37, whereas the rates were enhanced when the cells were depleted of the interleukin. Immunoblotting results showed that both exogenous and endogenous IL-37 could affect the expressions of RIPK3, NLRP3, and IL-1β. Also, the phosphorylation of RIPK3 and p65 was affected. Meanwhile, IL-37 promoted the transition of SMC from proliferative type to contractile type. Conclusions. The expression of IL-37 in VSMCs decreases in patients with AAA, whereas IL-37 supplementation suppresses RIPK3-mediated necroptosis and promotes the transition of VSMCs from proliferative to contractile type.

IL‑37 suppresses macrophage ferroptosis to attenuate diabetic atherosclerosis via the NRF2 pathway

“…This is one of the limitations to the current study. Previous studies have confirmed that IL-37 is a potential inhibitor of P65 and may exert anti-inflammatory effects by inhibiting the phosphorylation and nuclear translocation of P65 (39)(40)(41). P65 activation has also been suggested as a key mechanism for increased inflammation levels in diabetic atherosclerotic mice (42,43).…”

The intellectual base and research fronts of IL-37: A bibliometric review of the literature from WoSCC

“…The levels of IL-10 and TGF-b secreted by T cells isolated from patients were decreased in the treatment of rhIL-37 (91). Although the role of IL-37 in the animal model and clinical patients with atherosclerosis (93)(94)(95)(96), acute coronary syndrome (1,97), coronary artery calcification (98), coronary heart disease (99), chronic heart failure (100), atrial fibrillation (101), abdominal aortic aneurysm (102), hypertension (103), and other cardiovascular system diseases (91) has been identified, the timeline view of cocitation clusters revealed that the relationships between IL-37 and the cardiovascular system diseases remain the future hotspots. Cluster #0 seems to be the transfer of the second part of cluster #1 which has been undertaken in terms of research content.…”

Novel pharmacological approaches in abdominal aortic aneurysm

“…Mixed lineage kinase domain-like pseudokinase (MLKL) and calcium/calmodulin-dependent protein kinase II (CaMKII) are downstream effectors of RIP1-dependent necroptosis in AAA. Interestingly, pharmacological inhibition of necroptosis by targeting RIP1 or RIP3 ameliorates aneurysm expansion and even stabilises pre-existing aneurysms attenuating inflammation and inducing ECM repair [203,204], while, recently, the protective role of IL-37 on aneurysmal disease has been related to its ability to suppress RIP3-mediated necroptosis [205]. These findings have encouraged active research aiming at characterising the regulatory mechanisms underlying RIP3 upregulation in AAA [206], which will provide grounds for new therapeutic strategies for this disease.…”