Universität zu Köln

Eghbalzadeh, Kaveh, Georgi, Leena, Louis, Theresa, Zhao, Haizhi, Keser, Ugur, Weber, Carolyn, Mollenhauer, Martin, Conforti, Andreas, Wahlers, Thorsten and Paunel-Goerguelue, Adnana (2019). Compromised Anti-inflammatory Action of Neutrophil Extracellular Traps in PAD4-Deficient Mice Contributes to Aggravated Acute Inflammation After Myocardial Infarction. Front. Immunol., 10. LAUSANNE: FRONTIERS MEDIA SA. ISSN 1664-3224

Full text not available from this repository.

Abstract

Innate immune responses and rapid recruitment of leukocytes, which regulate inflammation and subsequent healing, play a key role in acute myocardial infarction (MI). Peptidylarginine deiminase 4 (PAD4) is critically involved in chromatin decondensation during the release of Neutrophil Extracellular Traps (NETs) by activated neutrophils. Alternatively, activated macrophages (M2) and accurate collagen deposition determine the repair of the infarcted heart. In this study, we investigated the impact of NETs on macrophage polarization and their role for acute cardiac inflammation and subsequent cardiac healing in a mouse model of acute MI. NETs were found to promote in vitro macrophage polarization toward a reparative phenotype. NETs suppressed pro-inflammatory macrophages (M1) under hypoxia and diminished IL-6 and TNF-alpha expression. Further on, NETs strongly supported M2b polarization and IL-10 expression. In cardiac fibroblasts, NETs increased TGF-beta expression under hypoxic culture conditions. PAD4(-/-) mice subjected to permanent ligation of the left anterior descending artery suffered from overwhelming inflammation in the acute phase of MI. Noteworthy, PAD4(-/-) neutrophils were unable to release NETs upon ex vivo stimulation with ionomycin or PMA, but produced significantly higher amounts of reactive oxygen species (ROS). Increased levels of circulating cell-free DNA, mitochondrial DNA and cardiac troponin were found in PAD4(-/-) mice in the acute phase of MI when compared to WT mice. Reduced cardiac expression of IL-6, IL-10, and M2 marker genes, as well as increased TNF-alpha expression, suggested a pro-inflammatory state. PAD4(-/-) mice displayed significantly increased cardiac MMP-2 expression under baseline conditions. At day 1, post-MI, PAD4(-/-) mice showed increased end-diastolic volume and increased thinning of the left ventricular wall. Interestingly, improved cardiac function, as demonstrated by significantly increased ejection fraction, was found at day 21. Altogether, our results indicate that NETs support macrophage polarization toward an M2 phenotype, thus displaying anti-inflammatory properties. PAD4 deficiency aggravates acute inflammation and increases tissue damage post-MI, partially due to the lack of NETs.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Eghbalzadeh, Kaveh UNSPECIFIED UNSPECIFIED UNSPECIFIED Georgi, Leena UNSPECIFIED UNSPECIFIED UNSPECIFIED Louis, Theresa UNSPECIFIED UNSPECIFIED UNSPECIFIED Zhao, Haizhi UNSPECIFIED UNSPECIFIED UNSPECIFIED Keser, Ugur UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Carolyn UNSPECIFIED UNSPECIFIED UNSPECIFIED Mollenhauer, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Conforti, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Wahlers, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Paunel-Goerguelue, Adnana UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-131932
DOI:	10.3389/fimmu.2019.02313
Journal or Publication Title:	Front. Immunol.
Volume:	10
Date:	2019
Publisher:	FRONTIERS MEDIA SA
Place of Publication:	LAUSANNE
ISSN:	1664-3224
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PEPTIDYLARGININE DEIMINASE 4; DEEP-VEIN THROMBOSIS; NF-KAPPA-B; CHROMATIN DECONDENSATION; REPERFUSION INJURY; MITOCHONDRIAL-DNA; HEART-FAILURE; IN-VIVO; MACROPHAGES; EXPRESSION Multiple languages Immunology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13193