Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis

Vajen, Tanja; Koenen, Rory R.; Werner, I.; Staudt, Mareike; Projahn, Delia; Curaj, Adelina; Sönmez, Tolga Taha; Simsekyilmaz, Sakine; Schumacher, David; Möllmann, Julia; Hackeng, Tilman M.; Hundelshausen, Philipp von; Weber, Christian; Liehn, Elisa A.

doi:10.1038/s41598-018-29026-0

Cited by 68 publications

(58 citation statements)

References 63 publications

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“…Neutralization of histone H4 led to a plaque stabilization, whereas blocking histone H2A or disrupting DNA structures by DNase had no effect on smooth muscle cells 120 . A significant decrease in infarction size and reduction of citrullinated histone 3 in infarcted tissue were demonstrated upon blocking of CCL5 and CXCL4 in mice, what was believed to be due to a reduced neutrophil recruitment 121 . In a model of myocardial infarction, Pad4 −/− mice were significantly protected from, whereas mice without PAD4 deficiency had myocardial injury with the presence of citrullinated histone H3 at the site of injury and increased plasma levels for nucleosomes 122 .…”

Section: Nets In Atherothrombosismentioning

confidence: 95%

In vivo evidence for extracellular DNA trap formation

et al. 2020

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Extracellular DNA trap formation is a cellular function of neutrophils, eosinophils, and basophils that facilitates the immobilization and killing of invading microorganisms in the extracellular milieu. To form extracellular traps, granulocytes release a scaffold consisting of mitochondrial DNA in association with granule proteins. As we understand more about the molecular mechanism for the formation of extracellular DNA traps, the in vivo function of this phenomenon under pathological conditions remains an enigma. In this article, we critically review the literature to summarize the evidence for extracellular DNA trap formation under in vivo conditions. Extracellular DNA traps have not only been detected in infectious diseases but also in chronic inflammatory diseases, as well as in cancer. While on the one hand, extracellular DNA traps clearly exhibit an important function in host defense, it appears that they can also contribute to the maintenance of inflammation and metastasis, suggesting that they may represent an interesting drug target for such pathological conditions. Facts •The demonstration of extracellular DNA traps in vivo requires sections of affected tissues, which are to be investigated with special staining techniques. These structures are seen in multiple inflammatory and cancer diseases.Is there a simple biomarker that reflects extracellular DNA trap formation?• What is the contribution of extracellular microbe killing compared to intracellular killing following phagocytosis?• The mechanism of DNA trap formation is unknown.

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Section: Nets In Atherothrombosismentioning

confidence: 95%

In vivo evidence for extracellular DNA trap formation

et al. 2020

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“…Their contribution has been found in, eg, cardiovascular diseases, strokes and many inflammatory and autoimmune diseases, as well as in brain damage. 103,[109][110][111][112][113][114] Increased expressions of chemokine genes in the brain can be caused not only by ischemia, but also by, eg, axonal damage or neurotoxins. 115 Although the contribution of chemokines to the pathogenesis of stroke has been demonstrated in both animal and human models, this issue still remains controversial.…”

Section: Selected Chemokines In Strokesmentioning

confidence: 99%

<p>The Role of Selected Pro-Inflammatory Cytokines in Pathogenesis of Ischemic Stroke</p>

Pawluk¹,

Woźniak²,

Grześk³

et al. 2020

CIA

139

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Stroke is currently one of the most common causes of death and disability in the world, and its pathophysiology is a complex process, involving the oxidative stress and inflammatory reaction. Unfortunately, no biochemical factors useful in the diagnostics and treatment of stroke have been clearly established to date. Therefore, researchers are increasingly interested in the inflammatory response triggered by cerebral ischemia and its role in the development of cerebral infarction. This article gives an overview of the available literature data concerning the role of pro-inflammatory cytokines in acute stroke. Detailed analysis of their role in cerebral circulation disturbances can also suggest certain immune response regulatory mechanisms aimed to reduce damage to the nervous tissue in the course of stroke.

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“…Upon adhesive contact with platelets, the CCL5/CXCL4 complex also triggers neutrophils to release NETs 58 and blocking the heterophilic interaction between CCL5 and CXCL4 was recently shown to prevent NETosis in a mouse model of myocardial infarction. 59 Vice versa, expelled NETs enhance the adhesion of additional platelets via von Willebrand factor 60,61 and promote their activation, thereby coordinating a pro-thrombotic cycle of coagulation and inflammation 56,60,62,63 (►Fig. 1B).…”

Section: Formation Of Neutrophil Extracellular Trapsmentioning

confidence: 99%

“…In line herewith, NETosis has emerged as an important contributor in a mouse model of myocardial ischaemia-reperfusion injury. 59,112 Neutrophils are able to produce a large array of cytokines, chemotactic factors and proteolytic enzymes and therefore play a role in inflammation, fibrogenesis and angiogenesis. 75,79 Thus, given the array of matrix-degrading enzymes that neutrophils contain, one can anticipate a destabilizing impact of neutrophils during thrombus evolution.…”

Section: Nets In Atherothrombosismentioning

confidence: 99%

Therapeutic Targeting of Neutrophil Extracellular Traps in Atherogenic Inflammation

2019

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Neutrophils and neutrophil extracellular traps (NETs) have a robust relationship with atherothrombotic disease risk, which led to the idea that interfering with the release of NETs therapeutically would ameliorate atherosclerosis. In human studies, acute coronary events and the pro-thrombotic state cause markedly elevated levels of circulating deoxyribonucleic acid (DNA) and chromatin, suggesting that DNase I might produce cardiovascular benefit. DNase I reproduced the phenotype of peptidylarginine deiminase 4 (PAD4) deficiency and showed a significant benefit for atherothrombotic disease in experimental mouse models. However, the mechanisms of benefit remain unclear. Insights into the mechanisms underlying NET release and atherogenic inflammation have come from transgenic mouse studies. In particular, the importance of neutrophil NET formation in promoting atherothrombotic disease has been shown and linked to profound pro-inflammatory and pro-thrombotic effects, complement activation and endothelial dysfunction. Recent studies have shown that myeloid deficiency of PAD4 leads to diminished NET formation, which in turn protects against atherosclerosis burden, propagation of its thrombotic complications and notably macrophage inflammation in plaques. In addition, oxidative stress and neutrophil cholesterol accumulation have emerged as important factors driving NET release, likely involving mitochondrial reactive oxidants and neutrophil inflammasome activation. Further elucidation of the mechanisms linking hyperlipidaemia to the release of NETs may lead to the development of new therapeutics specifically targeting atherogenic inflammation, with likely benefit for cardiovascular diseases.

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Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis

Cited by 68 publications

References 63 publications

In vivo evidence for extracellular DNA trap formation

In vivo evidence for extracellular DNA trap formation

<p>The Role of Selected Pro-Inflammatory Cytokines in Pathogenesis of Ischemic Stroke</p>

Therapeutic Targeting of Neutrophil Extracellular Traps in Atherogenic Inflammation

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