Expression of Toll-like receptor 4 is associated with enteroviral replication in human myocarditis

Satoh, Mamoru; Nakamura, Motoyuki; Akatsu, Tomonari; Iwasaka, Junji; Shimoda, Yudai; Segawa, Ikuo; Hiramori, Katsuhiko

doi:10.1042/cs20020263

Cited by 59 publications

(42 citation statements)

References 21 publications

(34 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…23 Our previous study has shown that increased expression of TLR4 is associated with EV replication in human myocarditis. 24 These reports suggest that activation of TLR4 may play an important role in host immune response against viral infection. In the present study, high levels of TLR4 mRNA expression were seen in DCM patients positive for both plus-and minus-strand EV RNA.…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor 4 is expressed with enteroviral replication in myocardium from patients with dilated cardiomyopathy

Satoh

Nakamura

Akatsu

et al. 2004

Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

Expressions of innate immune response proteins, most notably proinflammatory cytokines, against enteroviral (EV) infection have been documented in the heart of human dilated cardiomyopathy (DCM). Toll-like receptor 4 (TLR4) activates signaling pathways leading to the expression of proinflammatory cytokines implicated the etiology of DCM. We sought to determine whether EV replication activates TLR4-dependent immune response in myocardium obtained from patients with DCM. Endomyocardial biopsy tissues were obtained from 56 patients with DCM and 10 controls. Levels of plus-and minus-strand EV RNA and TLR4 mRNA were measured by real-time RT-PCR. Immunohistochemical analysis was performed to identify the cellular source of EV capsid protein VP1 and TLR4. Both plus-and minus-strand EV RNA were detected in 19 DCM patients (34%). Neither strand of EV RNA was detected in controls. TLR4 mRNA levels were higher in DCM patients than in controls (Po0.001). A positive correlation was found between TLR4 levels and each strand type of EV RNA in EV RNApositive patients (plus-strand vs TLR4: r ¼ 0.69, Po0.001; minus-strand vs TLR4: r ¼ 0.65, P ¼ 0.002). VP1/TLR4 double staining showed extensive colocalization of VP1 and TLR4 proteins in cytoplasm of cardiac myocytes in myocardium obtained from DCM patients. EV RNA-positive patients showed lower systolic function and larger ventricular volume compared with EV RNA-negative patients left ventricular ejection fraction (LVEF): P ¼ 0.002; left ventricular end-systolic diameter (LVESD): P ¼ 0.004). The DCM subgroup with high TLR4 levels showed lower LVEF and larger LVESD than the subgroup with TLR4 levels (both Po0.001). This study suggests that myocardial expression of TLR4 associates with EV replication in human DCM. EV RNA and TLR4 mRNA levels may correlate with LV dysfunction in DCM. The expression of TLR4 against EV replication may be involved in the pathogenesis of DCM.

show abstract

Section: Discussionmentioning

confidence: 99%

Toll-like receptor 4 is expressed with enteroviral replication in myocardium from patients with dilated cardiomyopathy

Satoh

Nakamura

Akatsu

et al. 2004

Laboratory Investigation

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, because cardiac myocytes also express TLR4, LPS could directly alter myocyte function. Studies have shown that myocyte TLR4 is functional in failing myocardium, 13 myocarditis, where TLR4 correlates to enteroviral replication and cardiac dysfunction, 14 and cytokine production within the heart of endotoxemic mice. 15 Interestingly, none of these studies has addressed which TLR4-positive cell types are responsible for the observed cardiac dysfunction.…”

mentioning

confidence: 99%

Immune Cell Toll-Like Receptor 4 Is Required for Cardiac Myocyte Impairment During Endotoxemia

Tavener

Long

Robbins

et al. 2004

Circulation Research

138

107

View full text Add to dashboard Cite

Abstract-The aim of this study was to investigate the importance of Toll-like receptor 4 (TLR4) signaling on cardiac myocytes versus immune cells in lipopolysaccharide (LPS)-induced cardiac dysfunction. Cardiac myocytes isolated from LPS-treated C57Bl/6 mice showed reduced shortening and calcium transients as compared with myocytes from untreated mice. In addition, LPS-treated C57Bl/6 mice showed impaired cardiac mitochondrial function, including reduced respiration and reduced time of induction of permeability transition. All of the aforementioned cardiac dysfunction was dependent on TLR4, because LPS-treated TLR4-deficient mice did not have reduced myocyte shortening or mitochondrial dysfunction. To evaluate the role of cardiac myocyte versus leukocyte TLR4, LPS was injected into chimeric mice with TLR4-positive leukocytes and TLR4-deficient myocytes. These mice showed reduced myocyte shortening in response to LPS. Myocytes from chimeric mice with TLR4-deficient leukocytes and TLR4-positive myocytes had no response to LPS. In addition, isolated myocytes from C57Bl/6 mice subsequently treated with LPS and serum for various times did not have reduced shortening, despite the presence of TLR4 mRNA and protein, as determined by reverse-transcription polymerase chain reaction and fluorescent-activated cell sorting. In fact, cardiac myocytes had equivalent amounts of TLR4 as endothelium; however, only the latter is responsive to LPS. Furthermore, signaling pathways downstream of TLR4 were not activated during direct LPS treatment of myocytes. In conclusion, TLR4 on leukocytes, and not on cardiac myocytes, is important for cardiac myocyte impairment during endotoxemia. Key Words: inflammation Ⅲ sepsis Ⅲ neutrophils Ⅲ heart Ⅲ contractility G ram-negative septicemia continues to elude effective treatment with 50% mortality, translating into the deaths of Ϸ400 000 North Americans per year. 1 One consistent result during the development of sepsis is the corresponding evolution of myocardial dysfunction. 2,3 Reduced cardiac contractile function has been observed in septic patients 4,5 and experimental animal models of lipopolysaccharide (LPS)-induced sepsis. 6 LPS, a cell membrane component shed from Gram-negative bacteria, is vital for the development of septicemia, but how LPS causes myocyte dysfunction remains largely unclear. Two paradigms are possible; the first involves direct activation and depression of myocytes via LPS, whereas the second would involve immune cells (nonmyocyte sources) including heart tissue macrophages, mast cells, and infiltrating blood leukocytes (neutrophils and monocytes) responding to LPS and depressing myocyte function. To date, most studies have examined cardiac responses after mice were treated with LPS, with clear evidence that LPS does have myocardial depressive properties. However, whether these were direct effects on the myocyte or indirect effects via nonmyocyte cells remains unclear. Finally, stimulation of cardiac myocytes directly with LPS has resulted in variable results includin...

show abstract

“…Our experimental findings strongly support a role for TLR2 as an initiator of cardiomyocyte hypertrophy triggered in response to T. cruzi as well as downstream events such as NF-B activation and IL-1␤ production. While cardiomyocytes are not normally associated with a role in host defense, accruing evidence indicates that these cells participate in cardiac surveillance, responding rapidly to endogenous indicators of stress through the activation of intrinsic Toll-like receptors (11,12,38). Our results highlight the potential for intrinsic cardiomyocyte TLRs to play a role in initiating a hypertrophic response following exposure to pathogens, pathogen products, or endogenous signals emanating from damaged cardiac muscle (11,12,38).…”

Section: Discussionmentioning

confidence: 74%

“…While cardiomyocytes are not normally associated with a role in host defense, accruing evidence indicates that these cells participate in cardiac surveillance, responding rapidly to endogenous indicators of stress through the activation of intrinsic Toll-like receptors (11,12,38). Our results highlight the potential for intrinsic cardiomyocyte TLRs to play a role in initiating a hypertrophic response following exposure to pathogens, pathogen products, or endogenous signals emanating from damaged cardiac muscle (11,12,38). The rapid onset of hypertrophy observed in cultured myocytes, within 24 to 48 h, suggests that physiologic changes in cardiomyocytes initiated by engagement of intrinsic TLRs in the heart, either locally or globally, may precede an inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 2 Regulates Interleukin-1β-Dependent Cardiomyocyte Hypertrophy Triggered by Trypanosoma cruzi

2005

View full text Add to dashboard Cite

Trypanosoma cruzi, the intracellular protozoan parasite that causes Chagasic cardiomyopathy, elicits a robust hypertrophic response in isolated cardiomyocytes. Previous studies established that T. cruzi-elicited cardiomyocyte hypertrophy is mediated by interleukin-1␤ produced by infected cardiomyocyte cultures. Here, we define key upstream signaling events leading to cardiomyocyte hypertrophy in response to T. cruzi infection, to be dependent on Toll-like receptor 2 and NF-B. Furthermore, we demonstrate that cardiomyocyte hypertrophy, which is initiated by live infective T. cruzi trypomastigotes or stimulation of isolated myocytes with secreted/released trypomastigote molecules, is a common outcome of the cardiomyocyte recognition of pathogen-associated molecular patterns by intrinsic Toll-like receptors. This study is the first to link pathogen recognition by intrinsic Toll-like receptors to cardiomyocyte hypertrophy.

show abstract

Expression of Toll-like receptor 4 is associated with enteroviral replication in human myocarditis

Cited by 59 publications

References 21 publications

Toll-like receptor 4 is expressed with enteroviral replication in myocardium from patients with dilated cardiomyopathy

Toll-like receptor 4 is expressed with enteroviral replication in myocardium from patients with dilated cardiomyopathy

Immune Cell Toll-Like Receptor 4 Is Required for Cardiac Myocyte Impairment During Endotoxemia

Toll-Like Receptor 2 Regulates Interleukin-1β-Dependent Cardiomyocyte Hypertrophy Triggered by Trypanosoma cruzi

Contact Info

Product

Resources

About