Neutrophil Extracellular Traps Induce the Epithelial-Mesenchymal Transition: Implications in Post-COVID-19 Fibrosis

Pandolfi, Laura; Beigrezaei, Sara; Frangipane, Vanessa; Percivalle, Elena; Luigi, Ada De; Violatto, Martina Bruna; Lopez, Gianluca; Gabanti, Elisa; Carsana, Luca; D’Amato, Maura; Morosini, Monica; Amici, Mara De; Nebuloni, Manuela; Fossali, Tommaso; Colombo, Riccardo; Saracino, Laura; Codullo, Veronica; Gnecchi, Massimiliano; Bigini, Paolo; Baldanti, Fausto; Lilleri, Daniele; Meloni, Federica

doi:10.3389/fimmu.2021.663303

Cited by 70 publications

(49 citation statements)

References 37 publications

(48 reference statements)

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“…In this study we show that the network of upregulated proteins is common across multiple cancer sub-types and largely distinguishes epithelial and mesenchymal forms of the disease (Figure 8). Moreover, such states are common to diabetes, neurodegenerative disorders, and infection driven syndromes – including severe COVID-19 (Lambert and Weinberg, 2021; Nieto et al, 2016; Pandolfi et al, 2021). This raises the possibility that cell shape changes which results in MTNO, and/or alter Kinesin-1 activity drive a common state which leads to different disease based on the cell of origin.…”

Section: Discussionmentioning

confidence: 99%

“…During differentiation from epithelial to mesenchymal forms, cells change from apicobasally polarized epithelial cuboidal cells with cell-cell adhesions such as adherens and tight junctions, to protrusive mesenchymal, fibroblast-type cells with leading edge polarity and the formation of extensive cell-ECM (Extracellular Matrix) adhesions. Dysregulation of EMP has been implicated in cancers, fibrotic diseases, aging related pathologies, and correlates with the severity of infection-driven sequelae such as those following COVID-19 infection (Lambert and Weinberg, 2021; Nieto et al, 2016; Pandolfi et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Arias-Garcia

Rickman

Sero

et al. 2019

Preprint

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The shape, size, and architecture of the nucleus determines the output of transcriptional programmes. As such, the ability of the nucleus to resist deformation and maintain its shape is essential for homeostasis. Conversely, changes in nuclear shape can alter transcription and cell state. The ability of cells to deform their nuclei is also essential for cells to invade confined spaces. But how cells set the extent of nuclear deformability in response to their environment is unclear. Here we show that the cell-cell adhesion protein JAM3 regulates nuclear shape. In epithelial cells, JAM3 is required for maintenance of nuclear shape by organizing microtubule polymers and promoting LMNA stabilization in the nuclear membrane. Depletion of JAM3 in normal epithelial cells leads to dysmorphic nuclei, which leads to differentiation into a mesenchymal-like state. Inhibiting the actions of kinesins in JAM3 depleted cells restores nuclear morphology and prevents differentiation into the mesenchymal-like state. Critically, JAM3 expression is predictive of disease progression. Thus JAM3 is a molecule which allows cells to control cell fates in response to the presence of neighbouring cells by tuning the extent of nuclear deformability. 3 IntroductionNuclear shape, size and architecture define the biophysics of key cellular processes such as transcription, replication, mRNA export, and DNA damage repair 1-4 . But nuclei are malleable viscoelastic structures 5, 6 that are frequently being stretched, strained, and compressed both by extracellular forces 7 , and the internal cytoskeleton 8-12 . Mechanisms have evolved to maintain nuclear shape and genome organization when cells are exposed to these forces 13 .Indeed, dysregulation of nuclear shape is coincident with numerous diseases including: muscular dystrophies, heart disease, and aging disorders such as progeria [14][15][16][17][18] . Thus in many cells, maintaining nuclear shape is essential for homeostasis.But while clearly maintenance of nuclear shape, size, and genome organization is essential for cellular homeostasis, transcriptional programmes that alter cell fate can be engaged by altering nuclear morphology and architecture 1,5,[19][20][21][22] . For example, nuclei undergo extensive shape changes that drive differentiation during development 23 . One means by which alteration in nuclear shape affects transcription is by affecting the nuclear translocation dynamics of transcription factors such as YAP/TAZ and NF-κB 24, 25 . Thus while in some cell types nuclear shape and genome organization are robust to deformation, in other cell types the nucleus is highly deformable.The importance of maintaining nuclear shape for cell, tissue, and organism homeostasis is highlighted by the fact that changes in nuclear morphology and genome organization are associated with cancer 4, 26 . For example, nuclear rupture is frequently an oncogenic event 27,28 . Indeed, pathologists have used nuclear shape as a diagnostic for over a century 29 . Irregular nuclear shapes and sizes are hall...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Arias-Garcia

Rickman

Sero

et al. 2019

Preprint

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“…Other study identified a variant on 3p21.31 region associated with increased respiratory failure risk in COVID-19 that enhances expression of leucine zipper transcription factor like 1 gene ( LZTFL1 ). LZTFL1 regulates a viral response pathway and is associated with epithelial-mesenchymal transition and it is possible that this epithelial dysfunction is driven by neutrophil extracellular traps ( 112 , 113 ).…”

Section: Nets Drive Thrombosis In Covid-19mentioning

confidence: 99%

On the Origin of Neutrophil Extracellular Traps in COVID-19

Pastorek

Celec

2022

Front. Immunol.

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Despite ongoing vaccination COVID-19 is a global healthcare problem because of the lack of an effective targeted therapy. In severe COVID-19 manifesting as acute respiratory distress syndrome, uncontrolled innate immune system activation results in cytokine deregulation, damage-associated molecular patterns release upon tissue damage and high occurrence of thrombotic events. These pathomechanisms are linked to neutrophil function and dysfunction, particularly increased formation of neutrophil extracellular traps (NETs). While the association of NETs and severity of COVID-19 has been shown and proved, the causes of NETs formation are unclear. The aim of this review is to summarize potential inducers of NETs formation in severe COVID-19 and to discuss potential treatment options targeting NETs formation of removal.

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“…A different study using post-mortem samples revealed increased levels of neutrophil extracellular traps (NET), which induce EMT in neighboring cells [73]. The increased presence of NETs positively correlates with the severity of COVID-19 and the elevated expression of EMT markers [74]. Importantly, a recent study showed that sera obtained from COVID-19 patients induce EMT in cancer cells, although the specific mechanism and whether SARS-CoV-2 makes patients more vulnerable to more aggressive forms of cancer remain to be determined [75].…”

Section: Cell Plasticity and Viral Infection: A Key Role For Emt In Virus-induced Cell Reprogrammingmentioning

confidence: 99%

An Integrated View of Virus-Triggered Cellular Plasticity Using Boolean Networks

Alfaro-García

Granados-Alzate

Vicente‐Manzanares

et al. 2021

Cells

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Virus-related mortality and morbidity are due to cell/tissue damage caused by replicative pressure and resource exhaustion, e.g., HBV or HIV; exaggerated immune responses, e.g., SARS-CoV-2; and cancer, e.g., EBV or HPV. In this context, oncogenic and other types of viruses drive genetic and epigenetic changes that expand the tumorigenic program, including modifications to the ability of cancer cells to migrate. The best-characterized group of changes is collectively known as the epithelial–mesenchymal transition, or EMT. This is a complex phenomenon classically described using biochemistry, cell biology and genetics. However, these methods require enormous, often slow, efforts to identify and validate novel therapeutic targets. Systems biology can complement and accelerate discoveries in this field. One example of such an approach is Boolean networks, which make complex biological problems tractable by modeling data (“nodes”) connected by logical operators. Here, we focus on virus-induced cellular plasticity and cell reprogramming in mammals, and how Boolean networks could provide novel insights into the ability of some viruses to trigger uncontrolled cell proliferation and EMT, two key hallmarks of cancer.

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Neutrophil Extracellular Traps Induce the Epithelial-Mesenchymal Transition: Implications in Post-COVID-19 Fibrosis

Cited by 70 publications

References 37 publications

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

Epithelial-Mesenchymal Plasticity is regulated by inflammatory signalling networks coupled to cell morphology

On the Origin of Neutrophil Extracellular Traps in COVID-19

An Integrated View of Virus-Triggered Cellular Plasticity Using Boolean Networks

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