Neutrophils Cast NETs in Atherosclerosis

Döring, Yvonne; Soehnlein, Oliver; Weber, Christian

doi:10.1161/circresaha.114.303479

Cited by 29 publications

(15 citation statements)

References 35 publications

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“…Monocytes/macrophages are the effector cells of the plaque associated chronic inflammation and a primary target in attempts to develop anti-inflammatory treatment options [2]. In the recent years disease modifying roles for neutrophils [3], T cells [4], and B cells [5] in plaque inflammation have been identified as well. Important factors that initiate, drive, and orchestrate the chronic inflammation are chemokines and cytokines.…”

Section: Introductionmentioning

confidence: 99%

Hyaluronan synthase 3 promotes plaque inflammation and atheroprogression

et al. 2018

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Objective Hyaluronan (HA) is a prominent component of the provisional extracellular matrix (ECM) present in the neointima of atherosclerotic plaques. Here the role of HA synthase 3 (HAS3) in atheroprogression was studied. Approach and results It is demonstrated here that HAS isoenzymes 1, -2 and -3 are expressed in human atherosclerotic plaques of the carotid artery. In Apolipoprotein E (Apoe)-deficient mice Has3 expression is increased early during lesion formation when macrophages enter atherosclerotic plaques. Importantly, HAS3 expression in vascular smooth muscle cells (VSMC) was found to be regulated by interleukin 1 β (IL-1β) in an NFkB dependent manner and blocking antibodies to IL-1β abrogate Has3 expression in VSMC by activated macrophages. Has3/Apoe double deficient mice developed less atherosclerosis characterized by decreased Th1-cell responses, decreased IL-12 release, and decreased macrophage-driven inflammation. Conclusions Inhibition of HAS3-dependent synthesis of HA dampens systemic Th1 cell polarization and reduces plaque inflammation. These data suggest that HAS3 might be a promising therapeutic target in atherosclerosis. Moreover, because HAS3 is regulated by IL-1β, our results suggest that therapeutic anti-IL-1β antibodies, recently tested in human clinical trials (CANTOS), may exert their beneficial effects on inflammation in post-myocardial infarction patients in part via effects on HAS3.

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Section: Introductionmentioning

confidence: 99%

Hyaluronan synthase 3 promotes plaque inflammation and atheroprogression

et al. 2018

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“…In systemic lupus erythematosus (SLE), a reduction in NET degradation due to the impaired functioning of DNase1 results in the progression of lupus nephritis (Hakkim et al, 2010), and in autoimmune small-vessel vasculitis, anti -neutrophil cytoplasmic antibody (ANCA) directly stimulates neutrophils to drive NET formation (Kessenbrock et al, 2009). In addition, the important role of NETs in the pathogenesis of atherosclerosis has been reported (Knight et al, 2014, Döring et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Lactoferrin Suppresses Neutrophil Extracellular Traps Release in Inflammation

et al. 2016

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Neutrophils are central players in the innate immune system. They generate neutrophil extracellular traps (NETs), which protect against invading pathogens but are also associated with the development of autoimmune and/or inflammatory diseases and thrombosis. Here, we report that lactoferrin, one of the components of NETs, translocated from the cytoplasm to the plasma membrane and markedly suppressed NETs release. Furthermore, exogenous lactoferrin shrunk the chromatin fibers found in released NETs, without affecting the generation of oxygen radicals, but this failed after chemical removal of the positive charge of lactoferrin, suggesting that charge-charge interactions between lactoferrin and NETs were required for this function. In a model of immune complex-induced NET formation in vivo, intravenous lactoferrin injection markedly reduced the extent of NET formation. These observations suggest that lactoferrin serves as an intrinsic inhibitor of NETs release into the circulation. Thus, lactoferrin may represent a therapeutic lead for controlling NETs release in autoimmune and/or inflammatory diseases.

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“…Elevated levels of NETs components such as cell free DNA (cfDNA), nucleosomes and neutrophil elastase in plasma was positively correlated to diabetes associated nephropathy and cardiovascular diseases15. NETs have also been shown to possess pro-thrombotic and atherogenic properties in the context of vascular diseases such as atherosclerosis1617 and stroke18.…”

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confidence: 99%

Elevated homocysteine levels in type 2 diabetes induce constitutive neutrophil extracellular traps

Joshi

Baipadithaya

Balakrishnan

et al. 2016

Sci Rep

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Constitutively active neutrophil extracellular traps (NETs) and elevated plasma homocysteine are independent risk factors for Type 2 Diabetes (T2D) associated vascular diseases. Here, we show robust NETosis due to elevated plasma homocysteine levels in T2D subjects and increased components of NETs such as neutrophil elastase and cell free DNA. Cooperative NETs formation was observed in neutrophils exposed to homocysteine, IL-6 and high glucose suggesting acute temporal changes tightly regulate constitutive NETosis. Homocysteine induced NETs by NADPH oxidase dependent and independent mechanisms. Constitutively higher levels of calcium and mitochondrial superoxides under hyperglycemic conditions were further elevated in response to homocysteine leading to accelerated NETosis. Homocysteine showed robust interaction between neutrophils and platelets by inducing platelet aggregation and NETosis in an interdependent manner. Our data demonstrates that homocysteine can alter innate immune function by promoting NETs formation and disturbs homeostasis between platelets and neutrophils which may lead to T2D associated vascular diseases.

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Neutrophils Cast NETs in Atherosclerosis

Cited by 29 publications

References 35 publications

Hyaluronan synthase 3 promotes plaque inflammation and atheroprogression

Hyaluronan synthase 3 promotes plaque inflammation and atheroprogression

Lactoferrin Suppresses Neutrophil Extracellular Traps Release in Inflammation

Elevated homocysteine levels in type 2 diabetes induce constitutive neutrophil extracellular traps

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