Transgenic Overexpression of IL-37 Protects Against Atherosclerosis and Strengthens Plaque Stability

Abstract

Background/Aims: Recently, studies have shown that interleukin-37 (IL-37) is involved in atherosclerosis-related diseases. However, the regulatory mechanisms of IL-37 in atherosclerosis remain unknown. This study aims to determine the role of IL-37 in atherosclerosis and to investigate the underlying mechanisms involved. Methods: IL-37 expression in human atherosclerotic plaques was detected by immunohistochemical staining and real-time reverse transcription polymerase chain reaction (RT-PCR). Oil Red O staining was used to measure the size of plaques. Cell apoptosis in vitro and in vivo was tested by flow cytometric analysis and terminal deoxynucleotidyl-transferase mediated dUTP nick-end labeling (TUNEL) staining, respectively. Protein expression levels of IL-37, IL-18Rα and p-Smad3 were measured by Weston blotting. Results: Immunohistochemical staining revealed that IL-37 was highly expressed in human atherosclerotic plaques. Intracellular cytokine staining revealed that infiltrated CD4⁺ T lymphocytes and vascular smooth muscle cells (VSMCs), but not macrophages, were the major sources of IL-37. Mice that overexpressed IL-37 exhibited significant improvements in their atherosclerotic burden, as demonstrated by reduced plaque size, increased collagen levels, and reduced numbers of apoptotic cells in vivo. Subsequently, mechanistic studies showed that IL-37 played an anti-atherosclerotic role, at least partially, through reducing inflammation by promoting the differentiation of the T helper cell anti-inflammatory phenotype, and through increasing plaque stability by decreasing matrix metalloproteinase (MMP)-2/13-mediated degradation of collagen and inhibiting VSMCs apoptosis. Conclusion: IL-37 may be a novel potential therapeutic target in patients with atherosclerotic heart disease.

IL-37 Exerts Anti-Inflammatory Effects in Fetal Membranes of Spontaneous Preterm Birth via the NF-κB and IL-6/STAT3 Signaling Pathway

“…However, no differences were found in MMP2 expression. According to the previous studies, IL-37 indeed affects MMP2 and MMP9 expressions in endometriosis, atherosclerosis, and human lung adenocarcinoma [40][41][42]. But why changes only occur in MMP9.…”

Inflammatory Cytokines During Cardiac Rehabilitation After Heart Surgery and Their Association to Postoperative Atrial Fibrillation

“…IL-33 is much greater and IL-37 much lower in all the patients' groups at T0 than in controls. IL-37 inhibits the expression of pro-inflammatory cytokines 28 and in mice exhibited significant improvements in the atherosclerotic burden 29 . Recently it has been suggested a possible role of IL-37 in human sera as a therapeutic agent or biomarker for the diagnosis of cardiovascular diseases 30 .…”

Cytokines at the Interplay Between Asthma and Atherosclerosis?

“…Another anti-inflammatory cytokine IL-37 expression was significantly reduced in the sputum of asthmatic children (Charrad et al, 2016), and was shown to be a key suppressor of asthma mediated mast cells (Conti et al, 2017) and airway inflammation and remodeling (Huang et al, 2018;Meng et al, 2019). IL-37 has also been found to exert athero-protective effects via the modulation of dendritic cell maturation, macrophage activation and by inducing Treg responses (Chai et al, 2015;Ji et al, 2017;McCurdy et al, 2017;Liu et al, 2018). Enhancing the activity of anti-inflammatory cytokines such as IL-10 and IL-37, which have protective roles in both disease states could be another potential avenue for pharmacological intervention for asthmatic patients who develop or are at high risk for developing CVD as a comorbidity.…”