A Review: The Significance of Toll-Like Receptors 2 and 4, and NF-κB Signaling in Endothelial Cells during Atherosclerosis

Atherosclerosis (AS) is a chronic inflammatory vascular disease that begins with endothelial activation followed by a series of inflammatory responses, plaque formation, and finally rupture. An early event in endothelial dysfunction is activation of the nuclear factor- $\kappa{}$ B (NF- $\kappa$ B) signaling axis. Toll-like receptors (TLRs) in endothelial cells (ECs) play an essential role in recognizing pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and lifestyle-associated molecular patterns (LAMPs). Activation of the canonical NF- $\kappa{}$ B pathway stimulates the expression of cytokines, chemokines, and an array of additional genes which activate and amplify AS-associated inflammatory responses. In this review, we discuss the involvement of TLR2/4 and NF- $\kappa{}$ B signaling in ECs during AS initiation, as well as regulation of the inflammatory response during AS by noncoding RNAs, especially microRNA (miRNA) and circular RNA (circRNA).

Keywords

TLR2

TLR4

NF-

\kappa{}

atherosclerosis

Funding

[2019]113-55(190826155555147)/Special Fund Project for Science and Technology Innovation Strategy of Guangdong Province

[2020]66 (ST2020027)/Shantou Medical Health Science and Technology Plan

Figures

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Fig. 1.

TLR2 and TLR4 signaling in endothelial cells and regulation of miRNAs. The transmission of toll-like receptor (TLR) signaling follows three steps. First, agonistic ligands mediate the formation of TLR2 heterodimers and TLR4 homodimers in the plasma membrane. These include pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) and lifestyle-associated molecular patterns (LAMPs). The TLR4 homodimers subsequently translocate from the cell surface to intracellular vesicles via endocytosis. Second, TLR2 heterodimers and TLR4 homodimers mediate assembly of the supramolecular organizing center (SMOC), including the Myddosome which governs MyD88-dependent signaling, and the Triffosome which governs TRIF-dependent signaling. TLR2 and TLR4 mediate assembly of the Myddosome, while TLR4 also mediates assembly of the Triffosome (black arrows). Third, SMOCs mediate the activation of kinases, which then activate the transcriptional response. The Myddosome activates the inhibitor of kappa B kinase (IKK)-related kinase Tumor necrosis factor receptor-associated factor (TRAF) family member associated Nuclear factor- $\kappa{}$ B (NF- $\kappa{}$ B) activator (TANK)-binding kinase 1 (TBK1), which in turn activates the kinase AKT (also known as PKB; protein kinase B). The kinase transforming growth factor b (TGF-b)-activated kinase 1 (TAK1) stimulates IKK-mediated activation of NF- $\kappa$ B and mitogen-activated protein kinase (MAPK)-mediated activation of activator protein-1 (AP-1). NF- $\kappa$ B not only stimulates the expression of additional immune genes, regulates downstream signal pathways (e.g., nod-like receptor protein 3 (NLRP3), proprotein convertase subtilisin/Kexin type 9 (PCSK9), induces cytokines and chemokines expression), but regulates microRNA (miRNA) expression. The Triffosome also activates TAK1 and mediates similar downstream responses, as well as activating TRAF3-dependent TBK1 which then activates interferon regulatory factor 4 (IRF4) leading to the interferon (IFN) response (green arrows). TLR signal transduction may be regulated by miRNAs at various levels (red arrows).

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Front. Biosci. (Landmark Ed) Print ISSN 2768-6701 Electronic ISSN 2768-6698