AUTHOR=Huangfu Ning , Wang Yong , Xu Zhenyu , Zheng Wenyuan , Tao Chunlan , Li Zhenwei , Hu Yewen , Chen Xiaomin 

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

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 9 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.687169

DOI=10.3389/fcell.2021.687169

ISSN=2296-634X

ABSTRACT=Objective:
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 of neurodegenerative diseases through triggering inflammatory response. This study investigated whether TDP43 is involved in AS development, especially in macrophages-mediated-foam cell formation and inflammatory responses is still unclear. 
Methods:
DP43 expressions in oxLDL-treated macrophages and peripheral blood mononuclear cells from patients with coronary artery disease were detected by RT-PCR, Western blot, and immunofluorescence. Gene gain or loss of functions was used to investigate the effects of TDP43 on macrophages-mediaded lipid untake and inflammation with ELISA，protein immunoprecipitation, RT-PCR, Western blot, and immunofluorescence. Macrophage TDP43 specific knockout mice with ApoE -/- background fed with western diet for 12 weeks to establish AS model, and used to explore the role of TDP43 on AS progression.
Results:
TDP43 expression increased in oxLDL-treated macrophages and peripheral blood mononuclear cells from patients with coronary artery disease. Furthermore, we find that TDP43 promotes activation of NF-κB to increase inflammatory factor expression in macrophages through triggering mitochondrial DNA release to activate cGAS-Sting signalling. Moreover, TDP43 strengthens lipid uptake of macrophages through regulating β-catenin and PPAR-γ complex to promote scavenger receptor gene CD36 transcription. Finally, using macrophage TDP43 specific knockout mice with ApoE -/- background fed with western diet for 12 weeks to establish AS model, we find that specific knockout of TDP43 in macrophages obviously alleviates western diet-induced AS progression in mice. 
Conclusions:
 
TDP43 exacerbates atherosclerosis progression by promoting inflammation and lipid uptake of macrophages, suggesting TDP43 as a potential target for developing atherosclerotic drug.