Thrombosis: tangled up in NETs

Martinod, Kimberly; Wagner, Denisa D.

doi:10.1182/blood-2013-10-463646

Cited by 693 publications

(665 citation statements)

References 123 publications

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“…Overall, this study confirms an important but different role for platelets, compared with that proposed previously in VT pathophysiology, and thereby provides further evidence for investigating antiplatelet therapy as prophylactic treatment against (recurrent) VT. 16,17 In recent years, neutrophils have been linked to a role in VT via a specialized cell death program in which NETs are released. 18,19 During thrombus formation in a mouse model of experimental VT, NETs released upon neutrophil recruitment to the (proinflammatory) vessel wall are indispensable. 1 The role of neutrophils became evident by using an antibody-mediated depletion strategy identical to the method used in this study (depletion of Ly6G-positive cells).…”

Section: Discussionmentioning

confidence: 99%

Role of platelets, neutrophils, and factor XII in spontaneous venous thrombosis in mice

Heestermans¹,

Salloum-Asfar²,

Salvatori³

et al. 2016

Blood

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Key Points• Platelets, neutrophils, and coagulation factor XII are implicated as important players in experimental venous thrombosis pathophysiology.• We demonstrate that platelets, but not neutrophils, are critical in spontaneous venous thrombosis, whereas low factor XII aggravates thrombosis.Recently, platelets, neutrophils, and factor XII (FXII) have been implicated as important players in the pathophysiology of venous thrombosis. Their role became evident in mouse models in which surgical handling was used to provoke thrombosis. Inhibiting anticoagulation in mice by using small interfering RNA (siRNA) targeting Serpinc1 and Proc also results in a thrombotic phenotype, which is spontaneous (no additional triggers) and reproducibly results in clots in the large veins of the head and fibrin deposition in the liver. This thrombotic phenotype is fatal but can be fully rescued by thrombin inhibition. The mouse model was used in this study to investigate the role of platelets, neutrophils, and FXII. After administration of siRNAs targeting Serpinc1 and Proc, antibody-mediated depletion of platelets fully abrogated the clinical features as well as microscopic aspects in the head. This was corroborated by strongly reduced fibrin deposition in the liver. Whereas neutrophils were abundant in siRNA-triggered thrombotic lesions, antibody-mediated depletion of circulating Ly6G-positive neutrophils did not affect onset, severity, or thrombus morphology. In addition, absence of circulating neutrophils did not affect quantitative liver fibrin deposition. Remarkably, siRNAmediated depletion of plasma FXII accelerated the onset of the clinical phenotype; mice were affected with more severe thrombotic lesions. To summarize, in this study, onset and severity of the thrombotic phenotype are dependent on the presence of platelets but not circulating neutrophils. Unexpectedly, FXII has a protective effect. This study challenges the proposed roles of neutrophils and FXII in venous thrombosis pathophysiology. (Blood. 2016;127(21):2630-2637

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Section: Discussionmentioning

confidence: 99%

Role of platelets, neutrophils, and factor XII in spontaneous venous thrombosis in mice

Heestermans¹,

Salloum-Asfar²,

Salvatori³

et al. 2016

Blood

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“…101 Circulating neutrophils get increasingly involved and contribute to thrombus formation via NET formation, 102 which is associated with local histone release. Extracellular histones elicit three different impacts: they kill microvascular endothelial cells, 74,92,103 trigger platelet activation and further thrombosis, 104 and activate innate immunity via TLRs and the NLRP3 inflammasome. 103,105 As a proof of principle, histone injection into the renal artery induces widespread TMA and renal cell necrosis.…”

Section: Rapidly Progressive Gnmentioning

confidence: 99%

Necroinflammation in Kidney Disease

Mulay

Linkermann

Anders

2016

Journal of the American Society of Nephrology

199

185

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The bidirectional causality between kidney injury and inflammation remains an area of unexpected discoveries. The last decade unraveled the molecular mechanisms of sterile inflammation, which established danger signaling via pattern recognition receptors as a new concept of kidney injury-related inflammation. In contrast, renal cell necrosis remained considered a passive process executed either by the complement-related membrane attack complex, exotoxins, or cytotoxic T cells. Accumulating data now suggest that renal cell necrosis is a genetically determined and regulated process involving specific outside-in signaling pathways. These findings support a unifying theory in which kidney injury and inflammation are reciprocally enhanced in an autoamplification loop, referred to here as necroinflammation. This integrated concept is of potential clinical importance because it offers numerous innovative molecular targets for limiting kidney injury by blocking cell death, inflammation, or both. Here, the contribution of necroinflammation to AKI is discussed in thrombotic microangiopathies, necrotizing and crescentic GN, acute tubular necrosis, and infective pyelonephritis or sepsis. Potential new avenues are further discussed for abrogating necroinflammation-related kidney injury, and questions and strategies are listed for further exploration in this evolving field.

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“…NETs have been characterized as proinflammatory, procoagulant and associated with a variety of thrombotic diseases. 4 The release of chromatin from neutrophils is driven by peptidylarginine deiminase 4 (PAD4), which in activated neutrophils translocates to the nucleus and through the citrullination of histones induces chromatin decondensation that is followed by chromatin release. 5 PAD4 is abundantly expressed in neutrophils, but is also upregulated in many cancers where it negatively regulates tumor suppressor genes of the p53 pathway and is thus involved in tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Priming of neutrophils toward NETosis promotes tumor growth

et al. 2016

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Neutrophils play a major role in cancer biology and both pro-and antitumoral functions of tumorinfiltrating neutrophils have been described. We have shown that tumors, by releasing G-CSF into the bloodstream, prime circulating neutrophils to form neutrophil extracellular traps (NETs) and we have detected the presence of NETs within the tumor microenvironment. Here, we report, using PAD4-deficient mice with a defect in neutrophil chromatin decondensation and NET formation, that the priming of neutrophils toward NETosis favors tumor growth. Interestingly, in a tumor model that does not release G-CSF and in which neutrophils are not primed for NETosis, PAD4-deficiency did not reduce tumor growth. However, supplying exogenous G-CSF to the wild-type (WT) host promoted intratumoral NETosis and tumor growth. Taken together, our results suggest that the priming of neutrophils for NETosis by the tumor or its environment leads to the accumulation of intratumoral NETs and a growth advantage to the tumor. Our work unveiled a pro-tumoral role for NETs which strengthens their potential as a new target in the fight against cancer.

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Thrombosis: tangled up in NETs

Cited by 693 publications

References 123 publications

Role of platelets, neutrophils, and factor XII in spontaneous venous thrombosis in mice

Role of platelets, neutrophils, and factor XII in spontaneous venous thrombosis in mice

Necroinflammation in Kidney Disease

Priming of neutrophils toward NETosis promotes tumor growth

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