Endothelial Cells as a Key Cell Type for Innate Immunity: A Focused Review on RIG-I Signaling Pathway

Abstract

The vascular endothelium consists of a highly heterogeneous monolayer of endothelial cells (ECs) which are the primary target for bacterial and viral infections due to EC's constant and close contact with the bloodstream. Emerging evidence has shown that ECs are a key cell type for innate immunity. Like macrophages, ECs serve as sentinels when sensing invading pathogens or microbial infection caused by viruses and bacteria. It remains elusive how ECs senses danger signals, transduce the signal and fulfil immune functions. Retinoic acid-inducible gene-I (RIG-I, gene name also known as DDX58) is an important member of RIG-I-like receptor (RLR) family that functions as an important pathogen recognition receptor (PRR) to execute immune surveillance and confer host antiviral response. Recent studies have demonstrated that virus infection, dsRNA, dsDNA, interferons, LPS, and 25-hydroxycholesterol (25-HC) can increase RIG-1 expression in ECs and propagate anti-viral response. Of translational significance, RIG-I activation can be inhibited by Panax notoginseng saponins, endogenous PPARγ ligand 15-PGJ2, tryptanthrin and 2-animopurine. Considering the pivotal role of inflammation and innate immunity in regulating endothelial dysfunction and atherosclerosis, here we provided a concise review of the role of RIG-I in endothelial cell function and highlight future direction to elucidate the potential role of RIG-I in regulating cardiovascular diseases as well as virus infectious disease, including COVID-19. Furthered understanding of RIG-I-mediated signaling pathways is important to control disorders associated with altered immunity and inflammation in ECs.

Keywords: DDX58; RIG-I; endothelial cells; immunity; inflammation.

Figure 1

Research trends of immune functions of endothelial cells. A literature search was performed in PubMed using subject terms: “Immune” OR “Immunity” AND “endothelial cell”. Data were retrieved on May 18, 2022.

Figure 2

(A) Domain structure of RIG-I like receptor (RLR). (B) Role of RIG-I in anti-viral response and endothelial dysfunction. LPS, lipopolysaccharide; oxLDL, oxidized LDL; TNFα, tumor necrosis factor α; IL-1β, interleukin 1 beta; RIG-I, retinoic acid-inducible gene I; MAVS, mitochondrial antiviral signaling; TBK1, TANK-binding kinase 1; IRF, interferon response factor; ISRE, interferon-sensitive responsive element; NF-κB, nuclear factor kappa B; STAT, signal transducer and activator of transcription; ISG, interferon-stimulated gene; IL-6, interleukin-6; IP-10 (also known as CXCL10), Interferon gamma-induced protein 10; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; 15-dPGJ2, 15-deoxy-delta-12,14-prostaglandin J2; ROS, reactive oxygen species; SASP, senescence-associated secretory phenotype; IFN, interferon; OAS2, 2’-5’-oligoadenylate synthetase 2; MDA5, melanoma differentiation-associated protein 5; LGP2, laboratory of genetics and physiology 2; CARD, caspase activation and recruitment domains; CTD, c-terminal domain. A, acetylation; P, phosphorylation; U, ubiquitination; S, SUMOylation.