Toll‐Like Receptor 9 Plays a Pivotal Role in Angiotensin II–Induced Atherosclerosis

Fukuda, Daiju; Nishimoto, Sei‐ichi; Aini, Kunduziayi; Tanaka, Atsushi; Nishiguchi, Tsuyoshi; Kim‐Kaneyama, Joo‐ri; Lei, Xiaofeng; Masuda, Kiyoshi; Naruto, Takuya; Tanaka, Kimie; Higashikuni, Yasutomi; Hirata, Yoichiro; Yagi, Shusuke; Kusunose, Kenya; Yamada, Hirotsugu; Soeki, Takeshi; Imoto, Issei; Akasaka, Takashi; Shimabukuro, Michio; Sata, Masataka

doi:10.1161/jaha.118.010860

Cited by 53 publications

(50 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Likewise, TLR7 and TLR9 appear to play protective roles because lipid aggregation, macrophage infiltration and accumulation, and production of pro-inflammatory cytokines are exacerbated in both Tlr7 −/− Apoe −/− and Tlr9 −/− Apoe −/− mice ( 52 , 53 , 54 ). In contrast, other groups have reported that TLR7 or TLR9 blockade may have beneficial effects in other murine atherosclerosis models by reducing scar tissue, lipid accumulation, macrophage infiltration, and plaque instability ( 55 , 56 , 57 ).…”

Section: Toll-like Receptorsmentioning

confidence: 86%

Innate Immune Receptors, Key Actors in Cardiovascular Diseases

Jaén

Val‐Blasco²,

Prieto

et al. 2020

JACC: Basic to Translational Science

View full text Add to dashboard Cite

show abstract

Section: Toll-like Receptorsmentioning

confidence: 86%

Innate Immune Receptors, Key Actors in Cardiovascular Diseases

Jaén

Val‐Blasco²,

Prieto

et al. 2020

JACC: Basic to Translational Science

View full text Add to dashboard Cite

show abstract

“…The pivotal role of TLR9 has recently been reported in angiotensin II-induced atherosclerosis. 18 There was increased circulating levels of cfDNA in angiotensin IIinfused ApoE -/mice whereas TLR9 blockade could suppress the proinflammatory activation of macrophages and vascular inflammation. 61 In addition, the activation of TLR9 has been indicated by hepatocyte mtDNA in driving nonalcoholic steatohepatitis.…”

Section: Cytoplasmic Mtdna Induced By Ecv Extract Could Activate Tlr9mentioning

confidence: 97%

“…17 Recently, evidence has accumulated to indicate that TLR9 plays a pivotal role in the development of vascular inflammation through proinflammatory activation of macrophages in angiotensin II-induced atherosclerosis. 18 In addition, pharmacological blockade of TLR9 can attenuate atherosclerotic lesion formation, suggesting TLR9 may serve as a potential therapeutic target for atherosclerosis. 18 TLR9 also recognizes endogenous self-DNA termed damage-associated molecular patterns (DAMPS) from injured mammalian cells.…”

Section: Introductionmentioning

confidence: 99%

“…18 In addition, pharmacological blockade of TLR9 can attenuate atherosclerotic lesion formation, suggesting TLR9 may serve as a potential therapeutic target for atherosclerosis. 18 TLR9 also recognizes endogenous self-DNA termed damage-associated molecular patterns (DAMPS) from injured mammalian cells. For example, mitochondrial DNA (mtDNA) is able to activate TLR9 and induces podocyte apoptosis.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Electronic cigarettes induce mitochondrial DNA damage and trigger toll-like receptor 9-mediated atherosclerosis

Huynh

Tang

et al. 2020

Preprint

View full text Add to dashboard Cite

Objective: Both electronic cigarette (e-cig) use and toll-like receptor 9 (TLR9) activation have been implicated in promoting atherosclerosis. In this study we aimed to investigate the causative relationship of e-cig exposure on TLR9 activation and atherosclerosis development. Approach and Results: Eight-week-old ApoE-/- mice fed normal chow diet were exposed to e-cig vapor (ECV) for 2 h/day, 5 days/week for 16 weeks. We found that ECV exposure significantly induced atherosclerotic lesions as examined by Oil Red O staining of aortic root and greatly upregulated TLR9 expression in classical monocytes and in the atherosclerotic plaques, which the latter was corroborated by upregulated TLR9 expression in human femoral artery atherosclerotic plaques in e-cig smokers. Intriguingly, we found a significant increase of damaged mitochondria DNA level in the circulating blood of ECV exposed mice. Furthermore, administration of TLR9 antagonist prior to ECV exposure not only alleviated atherosclerotic lesion and the upregulation of TLR9 in plaques, but also attenuated the increase of plasma levels of inflammatory cytokines, reduced the accumulation of lipid and macrophages, and decreased the frequency of blood CCR2+ classical monocytes. Surprisingly, we found that the cytoplasmic mtDNA isolated from ECV extract-treated cells can greatly enhance the expression of TLR9 in reporter cells. Conclusion: E-cig induces mtDNA damage and the mtDNA in circulating blood stimulates the expression of TLR9, which elevate the expression of proinflammatory cytokines in monocyte/macrophage and consequently lead to atherosclerosis. Our results raise the possibility that intervention of TLR9 activation is a potential pharmacologic target of ECV-related inflammation and cardiovascular diseases.

show abstract

“…In general, TLR9 activates IRFs and/or NF-κB, which produces interferons and cytokines, leading to the acceleration of inflammatory responses in these diseases [ 2 , 36 – 38 ]. In addition, other studies demonstrated that TLR9 promotes p38 mitogen-activated protein kinase (MAPK) activation and the subsequent NF-κB activation, stimulating inflammation [ 19 , 55 ]. On the other hand, a few studies reported that ligation of TLR9 with its ligand has beneficial effects on some disease context such as cerebral ischemia/reperfusion injury by activation of PI3K/Akt signaling [ 56 ].…”

Section: Role Of Tlr9 In Inflammatory Diseasesmentioning

confidence: 99%

Emerging roles of Toll-like receptor 9 in cardiometabolic disorders

2020

Self Cite

View full text Add to dashboard Cite

Growing evidence suggests that damage-associated molecule patterns (DAMPs) and their receptors, pattern recognition receptors (PRRs), are associated with the progression of cardiometabolic disorders, including obesity-related insulin resistance and atherosclerosis. Cardiometabolic disorders share sterile chronic inflammation as a major cause; however, the exact mechanisms are still obscure. Toll-like receptor 9 (TLR9), one of the nucleic acid-sensing TLRs, recognizes DNA fragments derived from pathogens and contributes to self-defense by activation of the innate immune system. In addition, previous studies demonstrated that TLR9 recognizes DNA fragments released from host cells, accelerating sterile inflammation, which is associated with inflammatory diseases such as autoimmune diseases. In obese adipose tissue and atherosclerotic vascular tissue, various stresses release DNA fragments and/or nuclear proteins as DAMPs from degenerated adipocytes and vascular cells. Recent studies indicated that the activation of TLR9 in immune cells including macrophages and dendritic cells by recognition of these DAMPs promotes inflammation in these tissues, which causes cardiometabolic disorders. This review discusses recent advances in understanding the role of sterile inflammation associated with TLR9 and its endogenous ligands in cardiometabolic disorders. New insights into innate immunity may provide better understanding of cardiometabolic disorders and new therapeutic options for these major health threats in recent decades.

show abstract

Toll‐Like Receptor 9 Plays a Pivotal Role in Angiotensin II–Induced Atherosclerosis

Cited by 53 publications

References 45 publications

Innate Immune Receptors, Key Actors in Cardiovascular Diseases

Innate Immune Receptors, Key Actors in Cardiovascular Diseases

Electronic cigarettes induce mitochondrial DNA damage and trigger toll-like receptor 9-mediated atherosclerosis

Emerging roles of Toll-like receptor 9 in cardiometabolic disorders

Contact Info

Product

Resources

About