PAD4-dependent NETs generation are indispensable for intestinal clearance of Citrobacter rodentium

Saha, Piu; Yeoh, Beng San; Xiao, Xia; Golonka, Rachel M.; Singh, Vishal; Wang, Yanming; Vijay‐Kumar, Matam

doi:10.1038/s41385-019-0139-3

Cited by 47 publications

(27 citation statements)

References 54 publications

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“…This includes cancer, chronic, autoimmune and neurodegenerative diseases [ 19 , 20 , 23 ], CNS injury [ 24 , 25 , 26 ] and ageing [ 27 , 28 ]. Importantly, roles for PADs have been described in viral [ 29 , 30 , 31 ] and other pathogenic infections, including sepsis, endotoxemia [ 29 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ] and antibiotic resistance [ 39 ]. The roles for PADs in anti-viral responses include PAD-mediated neutrophil extracellular trap formation (NETosis), for example, in respiratory syncytial virus disease [ 40 ].…”

Section: Introductionmentioning

confidence: 99%

Putative Roles for Peptidylarginine Deiminases in COVID-19

Arısan

Uysal-Onganer

Lange

2020

IJMS

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Peptidylarginine deiminases (PADs) are a family of calcium-regulated enzymes that are phylogenetically conserved and cause post-translational deimination/citrullination, contributing to protein moonlighting in health and disease. PADs are implicated in a range of inflammatory and autoimmune conditions, in the regulation of extracellular vesicle (EV) release, and their roles in infection and immunomodulation are known to some extent, including in viral infections. In the current study we describe putative roles for PADs in COVID-19, based on in silico analysis of BioProject transcriptome data (PRJNA615032 BioProject), including lung biopsies from healthy volunteers and SARS-CoV-2-infected patients, as well as SARS-CoV-2-infected, and mock human bronchial epithelial NHBE and adenocarcinoma alveolar basal epithelial A549 cell lines. In addition, BioProject Data PRJNA631753, analysing patients tissue biopsy data (n = 5), was utilised. We report a high individual variation observed for all PADI isozymes in the patients’ tissue biopsies, including lung, in response to SARS-CoV-2 infection, while PADI2 and PADI4 mRNA showed most variability in lung tissue specifically. The other tissues assessed were heart, kidney, marrow, bowel, jejunum, skin and fat, which all varied with respect to mRNA levels for the different PADI isozymes. In vitro lung epithelial and adenocarcinoma alveolar cell models revealed that PADI1, PADI2 and PADI4 mRNA levels were elevated, but PADI3 and PADI6 mRNA levels were reduced in SARS-CoV-2-infected NHBE cells. In A549 cells, PADI2 mRNA was elevated, PADI3 and PADI6 mRNA was downregulated, and no effect was observed on the PADI4 or PADI6 mRNA levels in infected cells, compared with control mock cells. Our findings indicate a link between PADI expression changes, including modulation of PADI2 and PADI4, particularly in lung tissue, in response to SARS-CoV-2 infection. PADI isozyme 1–6 expression in other organ biopsies also reveals putative links to COVID-19 symptoms, including vascular, cardiac and cutaneous responses, kidney injury and stroke. KEGG and GO pathway analysis furthermore identified links between PADs and inflammatory pathways, in particular between PAD4 and viral infections, as well as identifying links for PADs with a range of comorbidities. The analysis presented here highlights roles for PADs in-host responses to SARS-CoV-2, and their potential as therapeutic targets in COVID-19.

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Section: Introductionmentioning

confidence: 99%

Putative Roles for Peptidylarginine Deiminases in COVID-19

Arısan

Uysal-Onganer

Lange

2020

IJMS

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“…14 Recently, it has been shown that C. rodentium triggers NETosis in vitro and that NET formation is required for clearance in vivo. 15,16 Both NETosis and degranulation results in the release of reactive oxygen and nitrogen species (ROS and RNS), peroxidases including myeloperoxidase (MPO) and proteolytic enzymes such as neutrophil elastase (NE), cathepsin G and proteinase 3, which are contained within azurophilic granules. 17,18 These potent agents are unable to distinguish host cells from bacterial targets and if not tightly controlled have damaging consequences on host tissue.…”

Section: Introductionmentioning

confidence: 99%

Faecal neutrophil elastase-antiprotease balance reflects colitis severity

et al. 2020

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Given the global burden of diarrheal diseases on healthcare it is surprising how little is known about the drivers of disease severity. Colitis caused by infection and inflammatory bowel disease (IBD) is characterised by neutrophil infiltration into the intestinal mucosa and yet our understanding of neutrophil responses during colitis is incomplete. Using infectious (Citrobacter rodentium) and chemical (dextran sulphate sodium; DSS) murine colitis models, as well as human IBD samples, we find that faecal neutrophil elastase (NE) activity reflects disease severity. During C. rodentium infection intestinal epithelial cells secrete the serine protease inhibitor SerpinA3N to inhibit and mitigate tissue damage caused by extracellular NE. Mice suffering from severe infection produce insufficient SerpinA3N to control excessive NE activity. This activity contributes to colitis severity as infection of these mice with a recombinant C. rodentium strain producing and secreting SerpinA3N reduces tissue damage. Thus, uncontrolled luminal NE activity is involved in severe colitis. Taken together, our findings suggest that NE activity could be a useful faecal biomarker for assessing disease severity as well as therapeutic target for both infectious and chronic inflammatory colitis.

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“…Non‐DNA‐bound histones can subsequently break the nuclear envelope and plasma membranes 56 . The inability for PAD4‐deficient mice to form NETs in response to ionomycin shows the critical role PAD4 plays in this process 50,57 . In line with this, inhibition of PAD4 by the known PAD4 inhibitor Cl‐amidine significantly reduces histone citrullination and prevents the formation of NET‐like structures after stimulation of neutrophils with ionomycin 58 …”

Section: Pad4 In Net Formationmentioning

confidence: 95%

PAD4 takes charge during neutrophil activation: Impact of PAD4 mediated NET formation on immune‐mediated disease

Liu

Arfman

Wichapong

et al. 2021

Journal of Thrombosis and Haemostasis

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Background: Peptidyl arginine deiminase 4 (PAD4) is an enzyme that converts arginine into citrulline. PAD4 is expressed in neutrophils that, when activated, can drive the formation of neutrophil extracellular traps (NETs). Uncontrolled activation of PAD4 and subsequent citrullination of proteins is increasingly recognized as a driver of (auto)immune diseases. Currently, our understanding of PAD4 structure–function relationships and activity control in vivo is incomplete. Aims: To provide the current state‐of‐the‐art on PAD4 structure‐activity relationships and involvement of PAD4 in autoimmune disorders as well as in thrombo‐inflammatory disease. Materials & Methods: Literature review and molecular modelling Results: In this review, we used molecular modelling to generate a three‐dimensional structure of the complete PAD4 molecule. Using our model, we discuss the catalytic conversion of the arginine substrate to citrulline. Besides mechanistic insight into PAD4 function, we give an overview of biological functions of PAD4 and mechanisms that influence its activation. In addition, we discuss the crucial role of PAD4‐mediated citrullination of histones during the formation of NETs. Subsequently, we focus on the role of PAD4‐mediated NET formation and its role in pathogenesis of rheumatoid arthritis, sepsis and (immune‐)thrombosis. Finally, we summarize current efforts to design different classes of PAD4 inhibitors that are being developed for improved treatment of autoimmune disorders as well as thrombo‐inflammatory disease. Discussion: Advances in PAD4 structure‐function are still necessary to gain a complete insight in mechanisms that control PAD4 activity in vivo. The involvement of PAD4 in several diseases signifies the need for a PAD4 inhibitor. Although progress has been made to produce an isotype specific and potent PAD4 inhibitor, currently no PAD4 inhibitor is ready for clinical use. Conclusion: More research into PAD4 structure and function and into the regulation of its activity is required for the development of PAD4 specific inhibitors that may prove vital to combat and prevent autoimmune disorders and (thrombo)inflammatory disease.

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PAD4-dependent NETs generation are indispensable for intestinal clearance of Citrobacter rodentium

Cited by 47 publications

References 54 publications

Putative Roles for Peptidylarginine Deiminases in COVID-19

Putative Roles for Peptidylarginine Deiminases in COVID-19

Faecal neutrophil elastase-antiprotease balance reflects colitis severity

PAD4 takes charge during neutrophil activation: Impact of PAD4 mediated NET formation on immune‐mediated disease

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