Expansion of CD10neg neutrophils and HLA-DRneg/low monocytes driving inflammatory responses after myocardial infarction
Abstract
Background: Immature neutrophils and HLA-DRneg/low monocytes expand in cancer, autoimmune diseases and viral infections, but their appearance and immunoregulatory effects on T-cells after acute myocardial infarction (AMI) remain underexplored.
Methods and Results: We found an expansion of circulating immature CD16+CD66b+CD10neg neutrophils and CD14+HLA-DRneg/low monocytes in AMI patients, correlating with cardiac damage, function and levels of immune-inflammation markers. Immature CD10neg neutrophils expressed high amounts of MMP-9 and S100A9, and displayed resistance to apoptosis. Moreover, we found that increased frequency of CD10neg neutrophils and elevated circulating IFN-γ levels were linked, mainly in patients with expanded CD4+CD28null T-cells. Notably, the expansion of circulating CD4+CD28null T-cells was associated with cytomegalovirus (CMV) seropositivity. Using bioinformatic tools we identified a tight relationship among the peripheral expansion of immature CD10neg neutrophils, CMV IgG titers, and circulating levels of IFN-γ and IL-12 in patients with AMI. At a mechanistic level, CD10neg neutrophils enhanced IFN-γ production by CD4+ T-cells through a contact-independent mechanism involving IL-12. In vitro experiments also highlighted that HLA-DRneg/low monocytes do not suppress T-cell proliferation but secrete high levels of pro-inflammatory cytokines after differentiation to macrophages and IFN-γ stimulation. Lastly, using a mouse model of AMI, we showed that immature neutrophils (CD11bposLy6GposCD101neg cells) are recruited to the injured myocardium and migrate to mediastinal lymph nodes shortly after reperfusion.
Conclusions: Immunoregulatory functions of CD10neg neutrophils play a dynamic role in mechanisms linking myeloid cell compartment dysregulation, Th1-type immune responses and inflammation after AMI.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figure 1-figure supplement 1 and Figure 3-figure supplement 1.
Article and author information
Author details
Funding
Deutsche Forschungsgemeinschaft (BA 1742/8-1)
- Daniela Fraccarollo
Deutsche Forschungsgemeinschaft (BA 1742/8-1)
- Johann Bauersachs
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were conducted in accordance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (Publication No. 85-23, revised 1985). All procedures were approved by the Regierung von Unterfranken (Würzburg, Germany; permit No. 54-2531.01-15/07) and by the Niedersächsisches Landesamt für Verbraucherschutz und Lebensmittelsicherheit (Oldenburg, Germany; permit No. 33.12-42502-04-11/0644; 33.9-42502-04-13/1124 and 33.12-42502-04-17/2702).
Human subjects: The study protocol is in accordance with the ethical guidelines of the 1975 declaration of Helsinki and has been approved by the local ethics committee of Hannover Medical School. Patients referred to our department for acute coronary syndrome (ACS) were included after providing written informed consent.
Reviewing Editor
- Noriaki Emoto, Kobe Pharmaceutical University, Japan
Version history
- Preprint posted: September 21, 2020 (view preprint)
- Received: January 22, 2021
- Accepted: July 11, 2021
- Accepted Manuscript published: July 22, 2021 (version 1)
- Version of Record published: July 30, 2021 (version 2)
Copyright
© 2021, Fraccarollo et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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