Toll-Like Receptor-4 Modulates Survival by Induction of Left Ventricular Remodeling after Myocardial Infarction in Mice

Riad, Alexander; Jäger, Sebastian; Sobirey, Meike; Escher, Felicitas; Yaulema‐Riss, A.; Westermann, Dirk; Karatas, Aysun; Heimesaat, Markus M.; Bereswill, Stefan; Dragun, Duska; Pauschinger, Matthias; Schultheiß, Heinz Peter; Tschöpe, Carsten

doi:10.4049/jimmunol.180.10.6954

Cited by 114 publications

(74 citation statements)

References 53 publications

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“…This proinflammatory response included complement initiation, neutrophil infiltration, and ROS generation 23. TLR‐4–deficient mice exhibited a smaller infarct size with suppression of inflammatory reactions and less adverse remodeling following MI 31. However, the trigger of this response is unknown, and it is also not clear what activated TLR4 signaling after MI.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Apoptosis Inhibitor of Macrophage (AIM)/CD5L Attenuates the Inflammatory Response and Infarct Size in Acute Myocardial Infarction

Nishikido

Oyama

Shiraki

et al. 2016

JAHA

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BackgroundAn excessive inflammatory response after myocardial infarction (MI) increases myocardial injury. The toll‐like receptor (TLR)‐4 is activated by the recognition of endogenous ligands and is proinflammatory when there is myocardial tissue injury. The apoptosis inhibitor of the macrophage (AIM) is known to provoke an efflux of saturated free fatty acids (FFA) due to lipolysis, which causes inflammation via the TLR‐4 pathway. Therefore, this study investigated the hypothesis that AIM causes a proinflammatory response after MI.Methods and ResultsThe left anterior descending coronary artery was ligated to induce MI in both AIM‐knockout (AIM−/−) and wild‐type (WT) mice. After 3 days, the inflammatory response from activation of the TLR‐4/NFκB pathway was assessed, and infarct size was measured by staining with triphenyltetrazolium chloride. In addition, left ventricular remodeling was examined after 28 days. Although the area at risk was similar between AIM−/− and WT mice, the infarct size was significantly smaller in AIM−/− mice (P=0.02). The heart weight–to–body weight ratio and myocardial fibrosis were also decreased in the AIM−/− mice, and the 28‐day survival rate was improved (P<0.01). With the reduction of plasma FFA in AIM−/− mice, myocardial IRAK4 and NFκB activity were decreased (all P<0.05). Moreover, there was a reduction in myeloperoxidase activity and inducible nitric oxide synthase as part of the inflammatory response (P<0.01, P=0.03, respectively). Furthermore, NFκB DNA‐binding activation via TLR‐4, neutrophil infiltration, and inflammatory mediators were decreased in AIM−/− mice.ConclusionsThe deletion of AIM reduced the inflammatory response and infarct size and improved survival after myocardial infarction.

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Section: Discussionmentioning

confidence: 99%

Deletion of Apoptosis Inhibitor of Macrophage (AIM)/CD5L Attenuates the Inflammatory Response and Infarct Size in Acute Myocardial Infarction

Nishikido

Oyama

Shiraki

et al. 2016

JAHA

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“…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. In contrast, TLR2 null animals had similar infarct size and comparable inflammatory leukocyte infiltration with their wildtype littermates, but exhibited decreased fibrosis in the non-infarcted area and attenuated postinfarction ventricular remodeling [19].…”

Section: Tlr-mediated Pathwaysmentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

568

499

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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.

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“…Therefore, the possibility that a potential MI size reduction in TLR2 Ϫ/Ϫ mice compared with WT mice may contribute to the attenuated myocardial remodeling in TLR2 Ϫ/Ϫ animals needs to be ruled out. In a similar model of postinfarction remodeling, TLR4 was found to modulate survival as well as LV remodeling after ischemic injury (125,149). Although an enhanced JNK expression has been implicated as a possible intracellular mechanism for the attenuated LV remodeling in TLR4 Ϫ/Ϫ mice (125), the exact mechanisms as to how TLR2 and TLR4 signaling is initiated during myocardial ischemia and how they modulate subsequent ventricular remodeling remain elusive.…”

Section: Tlr Signaling Mediates Myocardial I/r Injurymentioning

confidence: 99%

Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

Chao¹

2009

American Journal of Physiology-Heart and Circulatory Physiology

212

166

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Toll-like receptors (TLRs) represent the first line of host defense against microbial infection and play a pivotal role in both innate and adaptive immunity. TLRs recognize invading pathogens through molecular pattern recognition, transduce signals via distinct intracellular pathways involving a unique set of adaptor proteins and kinases, and ultimately lead to the activation of transcription factors and inflammatory responses. Among 10 TLRs identified in humans, at least two exist in the heart, i.e., TLR2 and TLR4. In addition to the critical role of these in mediating cardiac dysfunction in septic conditions, emerging evidence suggests that the TLRs can also recognize endogenous ligands and may play an important role in modulating cardiomyocyte survival and in ischemic myocardial injury. In animal models of ischemia-reperfusion injury or in hypoxic cardiomyocytes in vitro, the administration of a sublethal dose of lipopolysaccharide, which signals through TLR4, reduces subsequent myocardial infarction, improves cardiac functions, and attenuates cardiomyocyte apoptosis. By contrast, a systemic deficiency of TLR2, TLR4, or myeloid differentiation primary-response gene 88, an adaptor critical for all TLR signaling, except TLR3, leads to an attenuated myocardial inflammation, a smaller infarction size, a better preserved ventricular function, and a reduced ventricular remodeling after ischemic injury. These loss-of-function studies suggest that both TLRs contribute to myocardial inflammation and ischemic injury in the heart although the exact contribution of cardiac (vs. circulatory cell) TLRs remains to be defined. These recent studies demonstrate an emerging role for TLRs as a critical modulator in both cell survival and tissue injury in the heart.

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Toll-Like Receptor-4 Modulates Survival by Induction of Left Ventricular Remodeling after Myocardial Infarction in Mice

Cited by 114 publications

References 53 publications

Deletion of Apoptosis Inhibitor of Macrophage (AIM)/CD5L Attenuates the Inflammatory Response and Infarct Size in Acute Myocardial Infarction

Deletion of Apoptosis Inhibitor of Macrophage (AIM)/CD5L Attenuates the Inflammatory Response and Infarct Size in Acute Myocardial Infarction

The immune system and cardiac repair

Toll-like receptor signaling: a critical modulator of cell survival and ischemic injury in the heart

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