TDP43 Exacerbates Atherosclerosis Progression by Promoting Inflammation and Lipid Uptake of Macrophages

• DOI: 10.3389/fcell.2021.687169
• Publication Date: 2021-07-05T08:21:21Z
• Authors: Ning Huangfu; Yong Wang; Zhenyu Xu; Wenyuan Zheng; Chunlan Tao; Zhenwei Li; Yewen Hu; Xiaomin Chen
• Keywords: Scavenger Receptor; CD36; Foam cell; Knockout mouse

Atherosclerosis (AS), characterized by cholesterol overloaded-macrophages accumulation and plaque formation in blood vessels, is the major cause of cardiovascular disease. Transactive response DNA-binding protein∼43 kDa (TDP43) has recently been identified as an independent driver neurodegenerative diseases through triggering inflammatory response. This study investigated whether TDP43 involved AS development, especially macrophages-mediated-foam cell responses.Transactive expressions oxidized low-density lipoprotein (oxLDL)-treated macrophages peripheral mononuclear cells (PBMCs) from patients with coronary artery disease (CAD) were detected real time-polymerase chain reaction (RT-PCR), Western blot, immunofluorescence. Gene gain or loss function was used to investigate effects on macrophages-mediated lipid untake inflammation ELISA, protein immunoprecipitation, RT-PCR, Macrophage specific knockout mice ApoE-/- background fed western diet for 12 weeks establish model, explore role progression.Transactive expression increases oxLDL-treated PBMCs CAD. Furthermore, we find that promotes activation NF-κB increase factor mitochondrial DNA release activate cGAS-STING signaling. Moreover, strengthens uptake regulating β-catenin PPAR-γ complex promote scavenger receptor gene CD36 transcription. Finally, using macrophage obviously alleviates diet-induced progression mice.Transactive exacerbates atherosclerosis promoting macrophages, suggesting a potential target developing atherosclerotic drug.