Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium

Frantz, Stefan; Kobzik, Lester; Kim, Young-Dae; Fukazawa, Ryuji; Medzhitov, Ruslan; Lee, Richard T.; Kelly, Ralph A.

doi:10.1172/jci6709

Cited by 592 publications

(435 citation statements)

References 47 publications

Supporting

Mentioning

399

Contrasting

Unclassified

Order By: Relevance

“…observed enhanced and predominantly sarcolemmal staining in the border zone, and scattered foci of intense TLR4 staining in adjacent regions of contiguous cardiomyocytes in the remote zone. In contrast, the infiltrating inflammatory cells exhibited no labelling for TLR4 12. Differently, Timmers et al .…”

Section: Discussionmentioning

confidence: 74%

“…The most common cause of CHF is ischaemic heart disease. The literature reports that TLR4 expression increases within days of MI 12, 14. We previously observed enhanced TLR4 expression after short‐term ischaemia in cultured cardiomyocytes, as well as intact heart 15.…”

Section: Introductionmentioning

confidence: 64%

“…However, little is known with respect to the functional status of TLRs in the failing heart, although TLR4 expression appears to be up‐regulated in the failing human heart 12, 13. The most common cause of CHF is ischaemic heart disease.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Liu

Yin

Cao

et al. 2015

J Cellular Molecular Medi

139

108

View full text Add to dashboard Cite

It remains unclear whether and how cardiomyocytes contribute to the inflammation in chronic heart failure (CHF). We recently reviewed the capacity of cardiomyocytes to initiate inflammation, by means of expressing certain immune receptors such as toll‐like receptors (TLRs) that respond to pathogen‐ and damage‐associated molecular patterns (PAMP and DAMP). Previous studies observed TLR4‐mediated inflammation within days of myocardial infarction (MI). This study examined TLR4 expression and function in cardiomyocytes of failing hearts after 4 weeks of MI in rats. The increases of TLR4 mRNA and proteins, as well as inflammatory cytokine production, were observed in both the infarct and remote myocardium. Enhanced immunostaining for TLR4 was observed in cardiomyocytes but not infiltrating leucocytes. The injection of lentivirus shRNA against TLR4 into the infarcted heart decreased inflammatory cytokine production and improved heart function in vivo. Accordingly, in cardiomyocytes isolated from CHF hearts, increases of TLR4 mRNA and proteins were detected. More robust binding of TLR4 with lipopolysaccharide (LPS), a PAMP ligand for TLR4, and heat shock protein 60 (HSP60), a DAMP ligand for TLR4, was observed in CHF cardiomyocytes under a confocal microscope. The maximum binding capacity (Bmax) of TLR4 was increased for LPS and HSP60, whereas the binding affinity (Kd) was not significantly changed. Furthermore, both LPS and HSP60 induced more robust production of inflammatory cytokines in CHF cardiomyocytes, which was reduced by TLR4‐blocking antibodies. We conclude that the expression, ligand‐binding capacity and pro‐inflammatory function of cardiomyocyte TLR4 are up‐regulated after long‐term MI, which promote inflammation and exacerbate heart failure.

show abstract

Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 64%

See 1 more Smart Citation

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Liu

Yin

Cao

et al. 2015

J Cellular Molecular Medi

139

108

View full text Add to dashboard Cite

show abstract

“…The unique TLR expression pattern, in particular the lack of TLR4 and the associated molecule MD2, suggests that the cervicovaginal epithelium is capable of responding to Gram-negative pathogens in the absence of endotoxin recognition. This is in contrast to the mechanism used by phagocytes (15,17,82), dendritic cells (83), and endothelial cells (51,84), which express TLR4 and are highly sensitive to LPS activation through the Toll/IL-1 signaling pathway.…”

Section: Discussionmentioning

confidence: 81%

Response toNeisseria gonorrhoeaeby Cervicovaginal Epithelial Cells Occurs in the Absence of Toll-Like Receptor 4-Mediated Signaling

Fichorova

Cronin

Lien

et al. 2002

The Journal of Immunology

212

174

View full text Add to dashboard Cite

Toll-like receptors (TLRs) have recently been identified as fundamental components of the innate immune response to bacterial pathogens. We investigated the role of TLR signaling in immune defense of the mucosal epithelial cells of the lower female genital tract. This site provides first line defense against microbial pathogens while remaining tolerant to a complex biosystem of resident microbiota. Epithelial cells derived from normal human vagina, ectocervix, and endocervix expressed mRNA for TLR1, -2, -3, -5, and -6. However, they failed to express TLR4 as well as MD2, two essential components of the receptor complex for LPS in phagocytes and endothelial cells. Consistent with this, endocervical epithelial cells were unresponsive to protein-free preparations of lipooligosaccharide from Neisseria gonorrhoeae and LPS from Escherichia coli. However, they were capable of responding to whole Gram-negative bacteria and bacterial lysates, as demonstrated by NF-κB activation and proinflammatory cytokine production. The presence of soluble CD14, a high-affinity receptor for LPS and other bacterial ligands, enhanced the sensitivity of genital tract epithelial cells to both low and high concentrations of bacteria, suggesting that soluble CD14 can act as a coreceptor for non-TLR4 ligands. These data demonstrate that the response to N. gonorrhoeae and other Gram-negative bacteria at the mucosal surface of the female genital tract occurs in the absence of endotoxin recognition and TLR4-mediated signaling.

show abstract

“…To date, 12 members of the TLR family have been identified in mammals; however, their role in cardiac pathology remains poorly understood. TLR4 is expressed in the heart and is markedly induced in mouse and rat infarcts and in samples obtained from cardiomyopathic hearts [16]. Recent investigations demonstrated that TLR4 deficient mice have decreased infarct size and suppressed inflammation [17], and exhibit attenuated adverse remodeling following myocardial infarction [18], identifying TLR4 as a key component of the innate immune response in the infarcted heart.…”

Section: Tlr-mediated Pathwaysmentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

568

499

View full text Add to dashboard Cite

Myocardial infarction is the most common cause of cardiac injury and results in acute loss of a large number of myocardial cells. Because the heart has negligible regenerative capacity, cardiomyocyte death triggers a reparative response that ultimately results in formation of a scar and is associated with dilative remodeling of the ventricle. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Toll Like Receptor-mediated pathways, the complement cascade and reactive oxygen generation induce Nuclear Factor (NF)-κB activation and upregulate chemokine and cytokine synthesis in the infarcted heart. Chemokines stimulate the chemotactic recruitment of inflammatory leukocytes into the infarct, while cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. Monocyte subsets play distinct roles in phagocytosis of dead cardiomyocytes and in granulation tissue formation through the release of growth factors. Clearance of dead cells and matrix debris may be essential for resolution of inflammation and transition into the reparative phase. Transforming Growth Factor (TGF)-β plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. Myofibroblast proliferation and angiogenesis result in formation of highly vascularized granulation tissue. As the healing infarct matures, fibroblasts become apoptotic and a collagen-based matrix is formed, while many infarct neovessels acquire a muscular coat and uncoated vessels regress. Timely resolution of the inflammatory infiltrate and spatial containment of the inflammatory and reparative response into the infarcted area are essential for optimal infarct healing. Targeting inflammatory pathways following infarction may reduce cardiomyocyte injury and attenuate adverse remodeling. In addition, understanding the role of the immune system in cardiac repair is necessary in order to design optimal strategies for cardiac regeneration.

show abstract

Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium

Cited by 592 publications

References 47 publications

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Up‐regulated TLR4 in cardiomyocytes exacerbates heart failure after long‐term myocardial infarction

Response toNeisseria gonorrhoeaeby Cervicovaginal Epithelial Cells Occurs in the Absence of Toll-Like Receptor 4-Mediated Signaling

The immune system and cardiac repair

Contact Info

Product

Resources

About