miR-146a is a pivotal regulator of neutrophil extracellular trap formation promoting thrombosis

Arroyo, Ana B.; Fernández-Pérez, María Piedad; Monte, Alberto del; Águila, Sonia; Méndez, Raúl; Hernández-Antolín, Rebecca; García-Barber, Nuria; Reyes-García, Ascensión M. de los; González-Jiménez, Paula; Arcas, María I; Vicente, Vicente; Menéndez, Rosário; Andrés, Vicente; Gónzález-Conejero, Rocío; Martı́nez, Constantino

doi:10.3324/haematol.2019.240226

Cited by 49 publications

(45 citation statements)

References 53 publications

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“…Furthermore, miR146a -/mice injected with LPS presented higher citH3 and thrombinantithrombin complex levels in plasma than WT and more severe lung injury. Based on these results miR-146a might have a role in immunothrombosis in septic patients 41 . The relationship between miR-146a levels and NETosis in sepsis evolution is an interesting field that we are exploring.…”

mentioning

confidence: 75%

“…Thus, all these findings support that miR-146a could be a useful agent for protection against sepsisinduced cardiac dysfunction. In fact, we have demonstrated an association between miR-146a rs2431697 genotype and risk for cardiovascular events in CAP patients 41 41 . Interestingly, our results pointed to NETosis as a functional way by which miR-146a levels lead to thrombosis in sepsis.…”

mentioning

confidence: 82%

“…miR-146a -/neutrophils also showed a lower expression of Cxcr1, that has been associated with a pro-inflammatory phenotype. All these features together with an increased formation of ROS observed in miR-146a -/mice, by a yet to discover mechanism, may explain in part why miR-146a deficiency increases NETosis 41 .…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…On the other hand, sterile stresses such as atherosclerosis and non-sterile such as endotoxemia produced an increased in NETosis in miR-146a -/mice vs. WT 40 . Although the precise mechanism is unknown, the lack of miR-146a provoked changes in neutrophils that display an aging phenotype characterized by the markers CD62L low CD11b high Cxcr4 high , and an overexpression of Tlr4 in the aged population 41 . miR-146a -/neutrophils also showed a lower expression of Cxcr1, that has been associated with a pro-inflammatory phenotype.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

“…Importantly, miR-146a is involved in NET formation although the precise mechanism is unknown 40,41 . Whether miR-146a affect other cells such as macrophages 115 or platelets 116 or processes that may affect NETosis have to be further searched.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

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miR-146a in Cardiovascular Diseases and Sepsis: An Additional Burden in the Inflammatory Balance?

et al. 2020

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The new concept of thrombosis associated with an inflammatory process is called thromboinflammation. Indeed, both thrombosis and inflammation interplay one with the other in a feed forward manner amplifying the whole process. This pathological reaction in response to a wide variety of sterile or non-sterile stimuli eventually causes acute organ damage. In this context, neutrophils, mainly involved in eliminating pathogens as an early barrier to infection, form neutrophil extracellular traps (NETs) that are antimicrobial structures responsible of deleterious side effects such as thrombotic complications. Although NETosis mechanisms are being unraveled, there are still many regulatory elements that have to be discovered. miRNAs are important modulators of gene expression implicated in human pathophysiology almost two decades ago. Among the different miRNAs implicated in inflammation, miR-146a is of special interest because: (i) it regulates among others, TLR/NF-B axis which is of paramount importance in inflammatory processes, (ii) it regulates the formation of NETs by modifying their ageing phenotype, (iii) it has expression levels that may decrease among individuals up to 50%, controlled in part by the presence of several polymorphisms. In this manuscript, we will review the main characteristics of miR-146a biology. In addition, we will detail how miR-146a is implicated in the development of two paradigmatic diseases in which thrombosis and inflammation interact, cardiovascular diseases and sepsis, and their association with the presence of miR-146a polymorphisms and the use of miR-146a as a marker of cardiovascular diseases and sepsis.

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confidence: 75%

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confidence: 82%

Section: Accepted Manuscriptmentioning

confidence: 99%

Section: Accepted Manuscriptmentioning

confidence: 99%

Section: Accepted Manuscriptmentioning

confidence: 99%

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miR-146a in Cardiovascular Diseases and Sepsis: An Additional Burden in the Inflammatory Balance?

et al. 2020

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Extracellular Vesicle Capture by AnTibody of CHoice and Enzymatic Release (EV‐CATCHER): A customizable purification assay designed for small‐RNA biomarker identification and evaluation of circulating small‐EVs

Mitchell

Ben‐Dov

Liu

et al. 2021

J of Extracellular Vesicle

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Circulating nucleic acids, encapsulated within small extracellular vesicles (EVs), provide a remote cellular snapshot of biomarkers derived from diseased tissues, however selective isolation is critical. Current laboratory‐based purification techniques rely on the physical properties of small‐EVs rather than their inherited cellular fingerprints. We established a highly‐selective purification assay, termed EV‐CATCHER, initially designed for high‐throughput analysis of low‐abundance small‐RNA cargos by next‐generation sequencing. We demonstrated its selectivity by specifically isolating and sequencing small‐RNAs from mouse small‐EVs spiked into human plasma. Western blotting, nanoparticle tracking, and transmission electron microscopy were used to validate and quantify the capture and release of intact small‐EVs. As proof‐of‐principle for sensitive detection of circulating miRNAs, we compared small‐RNA sequencing data from a subset of small‐EVs serum‐purified with EV‐CATCHER to data from whole serum, using samples from a small cohort of recently hospitalized Covid‐19 patients. We identified and validated, only in small‐EVs, hsa‐miR‐146a and hsa‐miR‐126‐3p to be significantly downregulated with disease severity. Separately, using convalescent sera from recovered Covid‐19 patients with high anti‐spike IgG titers, we confirmed the neutralizing properties, against SARS‐CoV‐2 in vitro, of a subset of small‐EVs serum‐purified by EV‐CATCHER, as initially observed with ultracentrifuged small‐EVs. Altogether our data highlight the sensitivity and versatility of EV‐CATCHER.

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Building a better NET: Neutrophil extracellular trap targeted therapeutics in the treatment of infectious and inflammatory disorders

Ngo

Gollomp

2022

Research and Practice in Thrombosis and Haemostasis

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Infectious and inflammatory stimuli induce the release of neutrophil extracellular traps (NETs), webs of cell‐free (cf) DNA complexed with histones and antimicrobial proteins, that capture and kill pathogens. Despite their protective role in the initial stages of sepsis, excessive NET release accompanied by NET degradation, leads to the release of NET degradation products (NDPs), including cfDNA, histones, and myeloperoxidase that injure the microvasculature. Murine studies have shown that clearance or neutralization of NDPs improves outcomes, demonstrating that NETs have a causal link to disease and are not merely biomarkers. Recently, elevated NDPs have been associated with disease severity in sepsis and coronavirus disease 2019, raising further interest in targeting NETs. Many propose eliminating NETs, either by preventing their release, or by degrading them. However, NET inhibition may impede the innate immune response and is difficult to achieve in rapid‐onset conditions such as sepsis. On the other hand, approaches that accelerate NET degradation have met with mixed results in murine studies, raising the concern that this strategy may liberate NET‐captured pathogens while increasing circulating levels of harmful NDPs. Alternative NET‐directed strategies include therapies that neutralize, sequester, or remove NDPs from the circulation. Others propose modifying released NETs to decrease their capacity to induce collateral tissue damage while enhancing their ability to capture microorganisms. Synthetic NETs have also been designed to combat antibiotic‐resistant organisms. Although it is still in its infancy, the field of NET‐targeted therapeutics is advancing rapidly and may soon find application in the treatment of sepsis and other inflammatory disorders.

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miR-146a is a pivotal regulator of neutrophil extracellular trap formation promoting thrombosis

Abstract: miR-146a is a pivotal regulator of neutrophil extracellular trap formation promoting thrombosis

Cited by 49 publications

References 53 publications

miR-146a in Cardiovascular Diseases and Sepsis: An Additional Burden in the Inflammatory Balance?

miR-146a in Cardiovascular Diseases and Sepsis: An Additional Burden in the Inflammatory Balance?

Extracellular Vesicle Capture by AnTibody of CHoice and Enzymatic Release (EV‐CATCHER): A customizable purification assay designed for small‐RNA biomarker identification and evaluation of circulating small‐EVs

Building a better NET: Neutrophil extracellular trap targeted therapeutics in the treatment of infectious and inflammatory disorders

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