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© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Neutrophil extracellular trap (NET)-formation represents an important defence mechanism for the rapid clearance of infections. However, exaggerated NET formation has been shown to negatively affect tissue-regeneration after injury. As our previous studies revealed the strong tissue-protective and regenerative properties of the secretome of stressed peripheral blood mononuclear cells (PBMCsec), we here investigated the influence of PBMCsec on the formation of NETs. The effect of PBMCsec on NET formation was assessed ex vivo in ionomycin stimulated neutrophils derived from healthy donors using flow cytometry, image stream analysis, and quantification of released extracellular DNA. The effect of PBMCsec on molecular mechanisms involved in NET formation, including Ca-flux, protein kinase C activity, reactive oxygen species production, and protein arginine deiminase 4 activity, were analysed. Our results showed that PBMCsec significantly inhibited NET formation. Investigation of the different biological substance classes found in PBMCsec revealed only a partial reduction in NET formation, suggesting a synergistic effect. Mechanistically, PBMCsec treatment did not interfere with calcium signalling and PKC-activation, but exerted anti-oxidant activity, as evidenced by reduced levels of reactive oxygen species and upregulation of heme oxygenase 1 and hypoxia inducible-factor 1 in PBMCsec-treated neutrophils. In addition, PBMCsec strongly inhibited the activation of protein arginine deiminase 4 (PAD4), ultimately leading to the inhibition of NET formation. As therapeutics antagonizing excessive NET formation are not currently available, our study provides a promising novel treatment option for a variety of conditions resulting from exaggerated NET formation.

Details

Title
The Effect of Paracrine Factors Released by Irradiated Peripheral Blood Mononuclear Cells on Neutrophil Extracellular Trap Formation
Author
Klas, Katharina 1 ; Ondracek, Anna S 2   VIAFID ORCID Logo  ; Hofbauer, Thomas M 2   VIAFID ORCID Logo  ; Mangold, Andreas 2 ; Pfisterer, Karin 3   VIAFID ORCID Logo  ; Laggner, Maria 1 ; Copic, Dragan 1   VIAFID ORCID Logo  ; Direder, Martin 1 ; Bormann, Daniel 1 ; Ankersmit, Hendrik Jan 1 ; Mildner, Michael 3   VIAFID ORCID Logo 

 Laboratory for Cardiac and Thoracic Diagnosis, Regeneration and Applied Immunology, Department of Thoracic Surgery, Medical University of Vienna, 1090 Vienna, Austria; Aposcience AG, 1200 Vienna, Austria 
 Division of Cardiology, Department of Internal Medicine II, Vienna General Hospital, Medical University of Vienna, 1090 Vienna, Austria 
 Department of Dermatology, Medical University of Vienna, 1090 Vienna, Austria 
First page
1559
Publication year
2022
Publication date
2022
Publisher
MDPI AG
e-ISSN
20763921
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2706103186
Copyright
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.