Extracellular histone H1 is neurotoxic and drives a pro-inflammatory response in microglia

Gilthorpe, Jonathan; Oozeer, Fazal; Nash, Julia A. B.; Calvo, Margarita; Bennett, David L.H.; Lumsden, Andrew; Pini, Adrian

doi:10.12688/f1000research.2-148.v1

Cited by 79 publications

(49 citation statements)

References 56 publications

(56 reference statements)

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“…Regarding the mechanisms of histone‐mediated cell death, caspase‐3 was activated in a small percentage of ECFCs, which correlated with the percentage of apoptosis observed by nuclear morphology examination. In this sense, apoptosis induction by histones has been described before in neurons, which undergo mitochondrial apoptosis after H1 treatment . In addition, TUNEL‐positive renal cells were significantly reduced in anti‐histone‐treated mice in a model of aggravated kidney injury .…”

Section: Discussionsupporting

confidence: 54%

Extracellular histones reduce survival and angiogenic responses of late outgrowth progenitor and mature endothelial cells

Mena

Carestia

Scotti

et al. 2016

Journal of Thrombosis and Haemostasis

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EssentialsExtracellular histones are highly augmented in sites of neovessel formation, such as regeneration tissues. We studied histone effect on survival and angiogenic activity of mature and progenitor endothelial cells. Extracellular histones trigger apoptosis and pyroptosis and reduce angiogenesis in vivo and in vitro. Histone blockade can be useful as a therapeutic strategy to improve angiogenesis and tissue regeneration.Summary. Background: Extracellular histones are highly augmented in sites of neovessel formation, like regeneration tissues. Their cytotoxic effect has been studied in endothelial cells, although the mechanism involved and their action on endothelial colony-forming cells (ECFCs) remain unknown. Objective: To study the effect of histones on ECFC survival and angiogenic functions and compare it with mature endothelial cells. Methods and Results: Nuclear morphology analysis showed that each human recombinant histone triggered both apoptotic-like and necrotic-like cell deaths in both mature and progenitor endothelial cells. While H1 and H2A exerted a weak toxicity, H2B, H3 and H4 were the most powerful. The percentage of apoptosis correlated with the percentage of ECFCs exhibiting caspase-3 activation and was zeroed by the pancaspase inhibitor Z-VAD-FMK. Necrotic-like cell death was also suppressed by this compound and the caspase-1 inhibitor Ac-YVAD-CMK, indicating that histones triggered ECFC pyroptosis. All histones, at non-cytotoxic concentrations, reduced migration and H2B, H3 and H4 induced cell cycle arrest and impaired tubulogenesis via p38 activation. Neutrophil-derived histones exerted similar effects. In vivo blood vessel formation in the quail chorioallantoic membrane was also reduced by H2B, H3 and H4. Their cytotoxic and antiangiogenic effects were suppressed by unfractioned and low-molecular-weight heparins and the combination of TLR2 and TLR4 blocking antibodies. Conclusions: Histones trigger both apoptosis and pyroptosis of ECFCs and inhibit their angiogenic functions. Their cytotoxic and antiangiogenic effects are similar in mature endothelial cells and disappear after heparin addition or TLR2/TLR4 blockade, suggesting both as therapeutic strategies to improve tissue regeneration.

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Section: Discussionsupporting

confidence: 54%

Extracellular histones reduce survival and angiogenic responses of late outgrowth progenitor and mature endothelial cells

Mena

Carestia

Scotti

et al. 2016

Journal of Thrombosis and Haemostasis

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“…Amyloid-β plaques in line with netting neutrophils are postulated to constitute another feedback loop amplifying neuroinflammation [36]. NET constituents can be harmful to neural cells within brain parenchyma, as they proteolytically cleave extracellular matrix proteins, activate inflammasome pathways and the mitochondrial apoptosis pathway [36,[44][45][46].…”

Section: Neurodegenerationmentioning

confidence: 99%

The Brain Entangled: The Contribution of Neutrophil Extracellular Traps to the Diseases of the Central Nervous System

Manda-Handzlik

Demkow

2019

Cells

115

100

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Under normal conditions, neutrophils are restricted from trafficking into the brain parenchyma and cerebrospinal fluid by the presence of the brain-blood barrier (BBB). Yet, infiltration of the central nervous system (CNS) by neutrophils is a well-known phenomenon in the course of different pathological conditions, e.g., infection, trauma or neurodegeneration. Different studies have shown that neutrophil products, i.e., free oxygen radicals and proteolytic enzymes, play an important role in the pathogenesis of BBB damage. It was recently observed that accumulating granulocytes may release neutrophil extracellular traps (NETs), which damage the BBB and directly injure surrounding neurons. In this review, we discuss the emerging role of NETs in various pathological conditions affecting the CNS.

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“…Inflammasomes that may cause both release of proinflammatory cytokines such as IL-1b and IL-18 and apoptotic or pyroptotic cell death are found in neurons (NLRP1 and AIM2), astrocytes (NLRP2) and microglia (NLRP3) (de Rivero Vaccari et al, 2014). Histone H1 released from dying cells of whatever type acts as an additional pro-inflammatory signal and chemoattractant (Gilthorpe et al, 2013). Moreover, stimulation of proinflammatory processes in different cell types implies the possibility of positive feedback loops between neurons, astrocytes and microglia that expand the grade and area of inflammation and may be further aggravated by recruitment of other immune cells.…”

Section: Neuronal Overexcitation and Microglia Activationmentioning

confidence: 99%

Melatonin and brain inflammaging

Hardeland¹,

Cardinali

Brown

et al. 2015

Progress in Neurobiology

166

164

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Melatonin is known to possess several properties of value for healthy aging, as a direct and indirect antioxidant, protectant and modulator of mitochondrial function, antiexcitotoxic agent, enhancer of circadian amplitudes, immune modulator and neuroprotectant. It is levels tend to decrease in the course of senescence and are more strongly reduced in several neurodegenerative disorders, especially Alzheimer's disease, and in diseases related to insulin resistance such as diabetes type 2. Although the role of melatonin in aging and age-related diseases has been repeatedly discussed, the newly emerged concept of inflammaging, that is, the contribution of low-grade inflammation to senescence progression has not yet been the focus of melatonin research. This review addresses the multiple protective actions of melatonin and its kynuramine metabolites that are relevant to the attenuation of inflammatory responses and progression of inflammaging in the brain, i.e. avoidance of excitotoxicity, reduction of free radical formation by support of mitochondrial electron flux, prevention of NADPH oxidase activation and suppression of inducible nitric oxide synthase, as well as downregulation of proinflammatory cytokines. The experimental evidence is primarily discussed on the basis of aging and senescence-accelerated animals, actions in the immune system, and the relationship between melatonin and sirtuins, having properties of aging suppressors. Sirtuins act either as accessory components or downstream factors of circadian oscillators, which are also under control by melatonin. Inflammaging is assumed to strongly contribute to neurodegeneration of the circadian master clock observed in advanced senescence and, even more, in Alzheimer's disease, a change that affects countless physiological functions.

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Extracellular histone H1 is neurotoxic and drives a pro-inflammatory response in microglia

Cited by 79 publications

References 56 publications

Extracellular histones reduce survival and angiogenic responses of late outgrowth progenitor and mature endothelial cells

Extracellular histones reduce survival and angiogenic responses of late outgrowth progenitor and mature endothelial cells

The Brain Entangled: The Contribution of Neutrophil Extracellular Traps to the Diseases of the Central Nervous System

Melatonin and brain inflammaging

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