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Regulation of toll-like receptor (TLR) signaling pathways in atherosclerosis: from mechanisms to targeted therapeutics

Acta Pharmacologica Sinica volume 44, pages 2358–2375 (2023)Cite this article

Abstract

Atherosclerosis, one of the life-threatening cardiovascular diseases (CVDs), has been demonstrated to be a chronic inflammatory disease, and inflammatory and immune processes are involved in the origin and development of the disease. Toll-like receptors (TLRs), a class of pattern recognition receptors that trigger innate immune responses by identifying pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), regulate numerous acute and chronic inflammatory diseases. Recent studies reveal that TLRs have a vital role in the occurrence and development of atherosclerosis, including the initiation of endothelial dysfunction, interaction of various immune cells, and activation of a number of other inflammatory pathways. We herein summarize some other inflammatory signaling pathways, protein molecules, and cellular responses associated with TLRs, such as NLRP3, Nrf2, PCSK9, autophagy, pyroptosis and necroptosis, which are also involved in the development of AS. Targeting TLRs and their regulated inflammatory events could be a promising new strategy for the treatment of atherosclerotic CVDs. Novel drugs that exert therapeutic effects on AS through TLRs and their related pathways are increasingly being developed. In this article, we comprehensively review the current knowledge of TLR signaling pathways in atherosclerosis and actively seek potential therapeutic strategies using TLRs as a breakthrough point in the prevention and therapy of atherosclerosis.

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Fig. 1: Structure of TLRs.
Fig. 2: TLR-related signaling pathways.
Fig. 3: Role of TLRs in the formation of AS.
Fig. 4: Schematic diagram illustrating the potential connection between and TLR signaling pathways and NLRP3 inflammasome-mediated pyroptosis and necroptosis.
Fig. 5: Drugs that exert therapeutic effects on AS through TLRs and their related pathways.

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Acknowledgements

This work is supported by National Natural Science Foundation of China (grant numbers 82270500, 81870324, 82203304, U21A20419), Science and Technology Project of Huadu District in Guangzhou (21-HDWS-007) and Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (grant numbers 2017BT01Y093, 2017BT01Y036).

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Author notes

  1. These authors contributed equally: Mei Jin and Jian Fang

Authors and Affiliations

  1. Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 511436, China

    Mei Jin, Jiao-jiao Wang, Pei-qing Liu, Wen-cai Ye & Zhi-ping Liu

  2. Affiliated Huadu Hospital, Southern Medical University (People’s Hospital of Huadu District), Guangzhou, 510800, China

    Jian Fang

  3. Department of Food Science and Engineering, Jinan University, Guangzhou, 511436, China

    Xin Shao

  4. Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230026, China

    Suo-wen Xu

  5. National-Local Joint Engineering Lab of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-sen University, Guangzhou, 510006, China

    Pei-qing Liu

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  1. Mei Jin
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Jin, M., Fang, J., Wang, Jj. et al. Regulation of toll-like receptor (TLR) signaling pathways in atherosclerosis: from mechanisms to targeted therapeutics. Acta Pharmacol Sin 44, 2358–2375 (2023). https://doi.org/10.1038/s41401-023-01123-5

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