Peptidylarginine deiminase 4 promotes age-related organ fibrosis

Martinod, Kimberly; Witsch, Thilo; Erpenbeck, Luise; Savchenko, A.S.; Hayashi, Hideki; Cherpokova, Deya; Gallant, Maureen; Mauler, Maximilian; Cifuni, Stephen M.; Wagner, Denisa D.

doi:10.1084/jem.20160530

Cited by 172 publications

(173 citation statements)

References 85 publications

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“…3 Elegant studies recently demonstrated that mice unable to form NETs are indeed protected from the development of fibrosis in the heart and lungs. 44 We found that the predominant protease within NETs, neutrophil elastase, is key to the induction of EndMT by NETs. Its mode of action involved the proteolysis of endothelial VE-cadherin, a known substrate of elastase, 23 and the subsequent activation of β-catenin signaling.…”

Section: Discussionmentioning

confidence: 74%

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

Pieterse

Rother

Garsen

et al. 2017

ATVB

192

150

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Objective— An excessive release and impaired degradation of neutrophil extracellular traps (NETs) leads to the continuous exposure of NETs to the endothelium in a variety of hematologic and autoimmune disorders, including lupus nephritis. This study aims to unravel the mechanisms through which NETs jeopardize vascular integrity. Approach and Results— Microvascular and macrovascular endothelial cells were exposed to NETs, and subsequent effects on endothelial integrity and function were determined in vitro and in vivo. We found that endothelial cells have a limited capacity to internalize NETs via the receptor for advanced glycation endproducts. An overflow of the phagocytic capacity of endothelial cells for NETs resulted in the persistent extracellular presence of NETs, which rapidly altered endothelial cell–cell contacts and induced vascular leakage and transendothelial albumin passage through elastase-mediated proteolysis of the intercellular junction protein VE-cadherin. Furthermore, NET-associated elastase promoted the nuclear translocation of junctional β-catenin and induced endothelial-to-mesenchymal transition in cultured endothelial cells. In vivo, NETs could be identified in kidney samples of diseased MRL/lpr mice and patients with lupus nephritis, in whom the glomerular presence of NETs correlated with the severity of proteinuria and with glomerular endothelial-to-mesenchymal transition. Conclusions— These results indicate that an excess of NETs exceeds the phagocytic capacity of endothelial cells for NETs and promotes vascular leakage and endothelial-to-mesenchymal transition through the degradation of VE-cadherin and the subsequent activation of β-catenin signaling. Our data designate NET-associated elastase as a potential therapeutic target in the prevention of endothelial alterations in diseases characterized by aberrant NET release.

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Section: Discussionmentioning

confidence: 74%

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

Pieterse

Rother

Garsen

et al. 2017

ATVB

192

150

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“…A brief collection of recent studies investigating potential impact of different leukocyte subsets in RILF is provided in supplemental Table S1, Supporting Information. Segregated‐nucleus‐containing atypical monocytes (SatM) with granulocyte characteristics regulated by CCAAT/enhancer binding protein β (C/EBPβ) as well as release of neutrophil extracellular traps (NETosis) consisting of extracellular chromatin orchestrated by peptidylarginine deiminase 4 (PAD4) in age related organ fibrosis . However, we found no dose dependent regulation of surrogates for SatM and NETosis on transcriptional and proteome level in our RILF model (data not shown).…”

Section: Discussionmentioning

confidence: 76%

Modeling and multiscale characterization of the quantitative imaging based fibrosis index reveals pathophysiological, transcriptome and proteomic correlates of lung fibrosis induced by fractionated irradiation

Zhou

Moustafa

Cao

et al. 2019

Intl Journal of Cancer

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Pulmonary fibrosis represents a leading cause of morbidity and mortality worldwide. Therapy induced lung fibrosis constitutes a pivotal dose‐limiting side effect of radiotherapy and other anticancer agents. We aimed to develop objective criteria for assessment of fibrosis and discover pathophysiological and molecular correlates of lung fibrosis as a function of fractionated whole thoracic irradiation. Dose–response series of fractionated irradiation was utilized to develop a non‐invasive and quantitative measure for the degree of fibrosis – the fibrosis index (FI). The correlation of FI with histopathology, blood‐gas, transcriptome and proteome responses of the lung tissue was analyzed. Macrophages infiltration and polarization was assessed by immunohistochemistry. Fibrosis development followed a slow kinetic with maximum lung fibrosis levels detected at 24‐week post radiation insult. FI favorably correlated with radiation dose and surrogates of lung fibrosis i.e., enhanced pro‐inflammatory response, tissue remodeling and extracellular matrix deposition. The loss of lung architecture correlated with decreased epithelial marker, loss of microvascular integrity with decreased endothelial and elevated mesenchymal markers. Lung fibrosis was further attributed to a switch of the inflammatory state toward a macrophage/T‐helper cell type 2‐like (M2/Th2) polarized phenotype. Together, the multiscale characterization of FI in radiation‐induced lung fibrosis (RILF) model identified pathophysiological, transcriptional and proteomic correlates of fibrosis. Pathological immune response and endothelial/epithelial to mesenchymal transition were discovered as critical events governing lung tissue remodeling. FI will be instrumental for deciphering the molecular mechanisms governing lung fibrosis and discovery of novel targets for treatment of this devastating disease with an unmet medical need.

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“…Furthermore, PAD4 −/− , a murine model incapable of NETosis, displays smaller infarct size and has significantly better heart function, demonstrated by an elevated ejection fraction subsequent to an ischemic event (14). In aged or diabetic mice, neutrophils are primed for NETosis, producing excessive thrombosis and inflammation (15). Myocardial NET deposition delays wound healing, leading to fibrosis in the cardiac pressure-overload model.…”

Section: Immunology Of Inflammation As It Pertains To the Vessel Wallmentioning

confidence: 99%

“…Intriguingly, spontaneous fibrosis of organs produced by aging is greatly reduced in PAD4 −/− mice. Functionally, PAD4 −/− hearts are comparable to young murine hearts, and their systolic and diastolic function does not decline with age (15). Thus, there is recent interest in further study of the specific roles of neutrophils, NETosis, and the PAD4 pathway in atherosclerosis.…”

Section: Immunology Of Inflammation As It Pertains To the Vessel Wallmentioning

confidence: 99%

Unraveling Vascular Inflammation

Teague

Ahlman

Alavi

et al. 2017

Journal of the American College of Cardiology

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Inflammation is a critical factor in early atherosclerosis and its progression to myocardial infarction. The search for valid surrogate markers of arterial vascular inflammation led to the increasing use of positron emission tomography (PET)–computed tomography. Indeed, vascular inflammation is associated with future risk of MI, and can be modulated with short-term therapies, such as statins, that mitigate cardiovascular risk. However, to better understand vascular inflammation and its mechanisms, we recently convened a panel of world experts in immunology, human translational research, and PET vascular imaging. This contemporary review first strives to understand the diverse roles of immune cells implicated in atherogenesis. Next, we describe human chronic inflammatory disease models that can help elucidate the pathophysiology of vascular inflammation. Finally, we review PET-based imaging techniques to characterize the vessel wall in vivo.

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Peptidylarginine deiminase 4 promotes age-related organ fibrosis

Cited by 172 publications

References 85 publications

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition

Modeling and multiscale characterization of the quantitative imaging based fibrosis index reveals pathophysiological, transcriptome and proteomic correlates of lung fibrosis induced by fractionated irradiation

Unraveling Vascular Inflammation

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