IL-37 Inhibits the Maturation of Dendritic Cells Through the IL1R8-TLR4-NF-κB Pathway

Abstract

Mature dendritic cells (DCs) play a pathogenic role in atherosclerosis. Our previous study demonstrated that exogenous interleukin (IL)-37 inhibits the maturation of DCs, induces the Tregulatory cell (Treg) response, and attenuates atherosclerosis in ApoE-/- mice. The aim of the present study was to investigate the molecular mechanism of IL-37 on the maturation of DCs during the development of atherosclerosis. The expression of IL-1R8, which is a single Ig-domain receptor that was recently found to be critical for the extracellular function of IL-37, TLR4 and p65, was measured in ApoE-/- mice and IL-37 transgenic (IL-37tg) ApoE-/- mice. IL-1R8 was mainly expressed in aortic plaque-infiltrated DCs and at significantly higher levels in IL-37tg atherosclerotic mice, accompanied by lower levels of TLR4 and p65. Furthermore, IL-37 eliminated the maturation of DCs induced by oxLDL and caused marked upregulation of IL-1R8 in vitro and downregulation of TLR4 and p65, which was consistent with the experiments in mice. However, the inhibitory effect of IL-37 on the maturation of DCs in vitro was abolished when IL37 was used to treat DCs isolated from IL-1R8-deficient and TLR4-deficient mice. Therefore, this study indicated that IL-37 inhibited the maturation of DCs via the IL-1R8-TLR4-NF-κB pathway and attenuated atherosclerosis in ApoE-/- mice. Funding Statement: This work was supported by the National Natural Science Foundation of China (No. 81560085, No.81370406). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: All mice were passed genetic identification and were maintained in the Animal Center of Tongji Medical College of Huazhong University of Science and Technology. The treatment and care of the animals were approved by the Animal Care and Utilization Committee of the People’s Hospital of Guangxi Zhuang Autonomous Region and Huazhong University of Science and Technology.