IL-6 in the infarcted heart is preferentially formed by fibroblasts and modulated by purinergic signaling

Alter, Christina; Henseler, Anne Sophie; Owenier, Christoph; Hesse, Julia; Ding, Zhaoping; Lautwein, Tobias; Bahr, Jasmin; Hayat, Sikander; Kramann, Rafael; Kostenis, Eva; Scheller, Jürgen; Schrader, Jürgen

doi:10.1172/jci163799

Cited by 18 publications

(10 citation statements)

References 64 publications

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“…With the deepening of research, new regulatory mechanisms of cardiac fibrosis will be revealed continuously. Consistent with previous study [ 17 ], our study reveals that fibroblasts also secrete large amounts of the inflammatory cytokine IL-6 after myocardial infarction or in response to DAMPs following myocardial infarction and confirms the important role of IL-6 produced by fibroblasts. We found that interfering with fibroblast IL-6 production significantly reduced fibroblast activation and inhibited pro-fibrotic cytokine IL-11 release mediated by STAT3.…”

Section: Discussionsupporting

confidence: 92%

“…Recently, it has also been shown that fibroblasts are also an important source of IL-6 after myocardial infarction. However, it remains unknown what role fibroblast-derived IL-6 plays in the function of fibroblasts [ 17 ]. Our study confirms that targeting fibroblast IL-6 expression also significantly improves cardiac dysfunction after myocardial infarction, providing evidence to support more precisely targeted therapy after infarction.…”

Section: Discussionmentioning

confidence: 99%

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Fibroblast-derived interleukin-6 exacerbates adverse cardiac remodeling after myocardial infarction

Li,

Bian

2024

Korean J Physiol Pharmacol

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Myocardial infarction is one of the leading causes of mortality globally. Currently, the pleiotropic inflammatory cytokine interleukin-6 (IL-6) is considered to be intimately related to the severity of myocardial injury during myocardial infarction. Interventions targeting IL-6 are a promising therapeutic option for myocardial infarction, but the underlying molecular mechanisms are not well understood. Here, we report the novel role of IL-6 in regulating adverse cardiac remodeling mediated by fibroblasts in a mouse model of myocardial infarction. It was found that the elevated expression of IL-6 in myocardium and cardiac fibroblasts was observed after myocardial infarction. Further, fibroblast-specific knockdown of Il6 significantly attenuated cardiac fibrosis and adverse cardiac remodeling and preserved cardiac function induced by myocardial infarction. Mechanistically, the role of Il6 contributing to cardiac fibrosis depends on signal transduction and activation of transcription (STAT)3 signaling activation. Additionally, Stat3 binds to the Il11 promoter region and contributes to the increased expression of Il11 , which exacerbates cardiac fibrosis. In conclusion, these results suggest a novel role for IL-6 derived from fibroblasts in mediating Stat3 activation and substantially augmented Il11 expression in promoting cardiac fibrosis, highlighting its potential as a therapeutic target for cardiac fibrosis.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Fibroblast-derived interleukin-6 exacerbates adverse cardiac remodeling after myocardial infarction

Li,

Bian

2024

Korean J Physiol Pharmacol

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“…In this issue of the JCI , Alter and colleagues elegantly implicated cardiac fibroblasts as a major source of IL-6 following coronary ligation in mice. ( 6 ) The study authors proposed a pathway that involved adenosine signaling to cardiac fibroblasts via the adenosine A2b receptor (A2bR) and provide supportive evidence from observations in human tissue.…”

Section: Cardiac Fibroblasts Produce Il-6mentioning

confidence: 61%

IL-6 helps weave the inflammatory web during acute coronary syndromes

Nakao¹,

Libby²

2023

Journal of Clinical Investigation

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The cytokine IL-6 has well-known proinflammatory roles in aging and ischemic heart disease. In this issue of the JCI , Alter and colleagues used mouse experiments and human tissue to investigate the source of IL-6 following myocardial infarction. The authors showed that cardiac fibroblasts produced IL-6 after coronary ligation in mice and proposed the existence of a pathway involving adenosine signaling via the adenosine A2b receptor. The findings underscore the complexity of IL-6 biology in ischemic heart disease and identify an adenosine/IL-6 pathway that warrants consideration for targeting as a modulator of cardiovascular risk.

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“…Also, 4-hour perfusion led to a 34% downregulated expression of IL-1β. Elevated levels of these markers are known to be associated with inflammatory responses, cardiac remodeling, and heart failure ( 22 , 23 ). However, their precise role in HMP and implications for clinical outcomes are yet to be delineated in future studies.…”

Section: Resultsmentioning

confidence: 99%

Novel portable hypothermic machine perfusion preservation device enhances cardiac viability of donated human hearts

Andrijauskaite,

Veraza,

Lopez

et al. 2024

Front. Cardiovasc. Med.

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IntroductionHeart transplant remains the gold standard treatment for patients with advanced heart failure. However, the list of patients waiting for a heart transplant continues to increase. We have developed a portable hypothermic oxygenated machine perfusion device, the VP.S ENCORE®, to extend the allowable preservation time. The purpose of this study was to test the efficacy of the VP.S. ENCORE® using deceased donors derived hearts.MethodsHearts from brain-dead donors not utilized for transplant (n = 11) were offered for research from the Texas Organ Sharing Alliance (TOSA), South and Central Texas' Organ Procurement Organization (OPO) and were preserved in the VP.S ENCORE® for 4 (n = 2), 6 (n = 3), and 8 (n = 3) hours or were kept in static cold storage (SCS) (n = 3). After preservation, the hearts were placed in an isolated heart Langendorff model for reperfusion and evaluated for cardiac function.ResultsThe mean donor age was 37.82 ± 12.67 with the youngest donor being 19 and the oldest donor being 58 years old. SCS hearts mean weight gain (%) was −1.4 ± 2.77, while perfused at 4 h was 5.6 ± 6.04, perfused at 6 h 2.1 ± 6.04, and 8 h was 7.2 ± 10.76. Venous and arterial lactate concentrations were less than 2.0 mmol/L across all perfused hearts. Left ventricular contractility (+dPdT, mmHg/s) for 4 h (1,214 ± 1,064), 6 (1,565 ± 141.3), and 8 h (1,331 ± 403.6) were within the range of healthy human heart function. Thus, not significant as compared to the SCS group (1,597 ± 342.2). However, the left ventricular relaxation (mmHg/s) was significant in 6-hour perfused heart (p < 0.05) as compared to SCS. Gene expression analysis of inflammation markers (IL-6, IL-1β) showed no significant differences between SCS and perfused hearts, but a 6-hour perfusion led to a downregulated expression of these markers.DiscussionThe results demonstrate that the VP.S ENCORE® device enhances cardiac viability and exhibits comparable cardiac function to a healthy heart. The implications of these findings suggest that the VP.S ENCORE® could introduce a new paradigm in the field of organ preservation, especially for marginal hearts.

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IL-6 in the infarcted heart is preferentially formed by fibroblasts and modulated by purinergic signaling

Cited by 18 publications

References 64 publications

Fibroblast-derived interleukin-6 exacerbates adverse cardiac remodeling after myocardial infarction

Fibroblast-derived interleukin-6 exacerbates adverse cardiac remodeling after myocardial infarction

IL-6 helps weave the inflammatory web during acute coronary syndromes

Novel portable hypothermic machine perfusion preservation device enhances cardiac viability of donated human hearts

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