The cardiac microenvironment uses non‐canonical WNT signaling to activate monocytes after myocardial infarction
Abstract A disturbed inflammatory response following myocardial infarction (MI) is associated with poor prognosis and increased tissue damage. Monocytes are key players in healing after MI, but little is known about the role of the cardiac niche in monocyte activation. This study investigated microe...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2017-09-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201707565 |
| _version_ | 1797280441267388416 |
|---|---|
| author | Ingmar Sören Meyer Andreas Jungmann Christoph Dieterich Min Zhang Felix Lasitschka Susann Werkmeister Jan Haas Oliver J Müller Michael Boutros Matthias Nahrendorf Hugo A Katus Stefan E Hardt Florian Leuschner |
| author_facet | Ingmar Sören Meyer Andreas Jungmann Christoph Dieterich Min Zhang Felix Lasitschka Susann Werkmeister Jan Haas Oliver J Müller Michael Boutros Matthias Nahrendorf Hugo A Katus Stefan E Hardt Florian Leuschner |
| author_sort | Ingmar Sören Meyer |
| collection | DOAJ |
| description | Abstract A disturbed inflammatory response following myocardial infarction (MI) is associated with poor prognosis and increased tissue damage. Monocytes are key players in healing after MI, but little is known about the role of the cardiac niche in monocyte activation. This study investigated microenvironment‐dependent changes in inflammatory monocytes after MI. RNA sequencing analysis of murine Ly6Chigh monocytes on day 3 after MI revealed differential regulation depending on location. Notably, the local environment strongly impacted components of the WNT signaling cascade. Analysis of WNT modulators revealed a strong upregulation of WNT Inhibitory Factor 1 (WIF1) in cardiomyocytes—but not fibroblasts or endothelial cells—upon hypoxia. Compared to wild‐type (WT) littermates, WIF1 knockout mice showed severe adverse remodeling marked by increased scar size and reduced ejection fraction 4 weeks after MI. While FACS analysis on day 1 after MI revealed no differences in neutrophil numbers, the hearts of WIF1 knockouts contained significantly more inflammatory monocytes than hearts from WT animals. Next, we induced AAV‐mediated cardiomyocyte‐specific WIF1 overexpression, which attenuated the monocyte response and improved cardiac function after MI, as compared to control‐AAV‐treated animals. Finally, WIF1 overexpression in isolated cardiomyocytes limited the activation of non‐canonical WNT signaling and led to reduced IL‐1β and IL‐6 expression in monocytes/macrophages. Taken together, we investigated the cardiac microenvironment's interaction with recruited monocytes after MI and identified a novel mechanism of monocyte activation. The local initiation of non‐canonical WNT signaling shifts the accumulating myeloid cells toward a pro‐inflammatory state and impacts healing after myocardial infarction. |
| first_indexed | 2024-03-07T16:41:14Z |
| format | Article |
| id | doaj.art-5849c9afcb14451aae01f76bf3c5ab64 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T16:41:14Z |
| publishDate | 2017-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-5849c9afcb14451aae01f76bf3c5ab642024-03-03T08:12:08ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-09-01991279129310.15252/emmm.201707565The cardiac microenvironment uses non‐canonical WNT signaling to activate monocytes after myocardial infarctionIngmar Sören Meyer0Andreas Jungmann1Christoph Dieterich2Min Zhang3Felix Lasitschka4Susann Werkmeister5Jan Haas6Oliver J Müller7Michael Boutros8Matthias Nahrendorf9Hugo A Katus10Stefan E Hardt11Florian Leuschner12Department of Medicine III University of Heidelberg Heidelberg GermanyDepartment of Medicine III University of Heidelberg Heidelberg GermanyDepartment of Medicine III University of Heidelberg Heidelberg GermanyDepartment of Medicine III University of Heidelberg Heidelberg GermanyInstitute of Pathology University of Heidelberg Heidelberg GermanyDepartment of Medicine III University of Heidelberg Heidelberg GermanyDepartment of Medicine III University of Heidelberg Heidelberg GermanyDepartment of Medicine III University of Heidelberg Heidelberg GermanyDZHK (German Centre for Cardiovascular Research), Partnersite Heidelberg/Mannheim GermanyCenter for Systems Biology Massachusetts General Hospital and Harvard Medical School Boston MA USADepartment of Medicine III University of Heidelberg Heidelberg GermanyDepartment of Medicine III University of Heidelberg Heidelberg GermanyDepartment of Medicine III University of Heidelberg Heidelberg GermanyAbstract A disturbed inflammatory response following myocardial infarction (MI) is associated with poor prognosis and increased tissue damage. Monocytes are key players in healing after MI, but little is known about the role of the cardiac niche in monocyte activation. This study investigated microenvironment‐dependent changes in inflammatory monocytes after MI. RNA sequencing analysis of murine Ly6Chigh monocytes on day 3 after MI revealed differential regulation depending on location. Notably, the local environment strongly impacted components of the WNT signaling cascade. Analysis of WNT modulators revealed a strong upregulation of WNT Inhibitory Factor 1 (WIF1) in cardiomyocytes—but not fibroblasts or endothelial cells—upon hypoxia. Compared to wild‐type (WT) littermates, WIF1 knockout mice showed severe adverse remodeling marked by increased scar size and reduced ejection fraction 4 weeks after MI. While FACS analysis on day 1 after MI revealed no differences in neutrophil numbers, the hearts of WIF1 knockouts contained significantly more inflammatory monocytes than hearts from WT animals. Next, we induced AAV‐mediated cardiomyocyte‐specific WIF1 overexpression, which attenuated the monocyte response and improved cardiac function after MI, as compared to control‐AAV‐treated animals. Finally, WIF1 overexpression in isolated cardiomyocytes limited the activation of non‐canonical WNT signaling and led to reduced IL‐1β and IL‐6 expression in monocytes/macrophages. Taken together, we investigated the cardiac microenvironment's interaction with recruited monocytes after MI and identified a novel mechanism of monocyte activation. The local initiation of non‐canonical WNT signaling shifts the accumulating myeloid cells toward a pro‐inflammatory state and impacts healing after myocardial infarction.https://doi.org/10.15252/emmm.201707565inflammationmonocytesmyocardial infarction |
| spellingShingle | Ingmar Sören Meyer Andreas Jungmann Christoph Dieterich Min Zhang Felix Lasitschka Susann Werkmeister Jan Haas Oliver J Müller Michael Boutros Matthias Nahrendorf Hugo A Katus Stefan E Hardt Florian Leuschner The cardiac microenvironment uses non‐canonical WNT signaling to activate monocytes after myocardial infarction EMBO Molecular Medicine inflammation monocytes myocardial infarction |
| title | The cardiac microenvironment uses non‐canonical WNT signaling to activate monocytes after myocardial infarction |
| title_full | The cardiac microenvironment uses non‐canonical WNT signaling to activate monocytes after myocardial infarction |
| title_fullStr | The cardiac microenvironment uses non‐canonical WNT signaling to activate monocytes after myocardial infarction |
| title_full_unstemmed | The cardiac microenvironment uses non‐canonical WNT signaling to activate monocytes after myocardial infarction |
| title_short | The cardiac microenvironment uses non‐canonical WNT signaling to activate monocytes after myocardial infarction |
| title_sort | cardiac microenvironment uses non canonical wnt signaling to activate monocytes after myocardial infarction |
| topic | inflammation monocytes myocardial infarction |
| url | https://doi.org/10.15252/emmm.201707565 |
| work_keys_str_mv | AT ingmarsorenmeyer thecardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT andreasjungmann thecardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT christophdieterich thecardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT minzhang thecardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT felixlasitschka thecardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT susannwerkmeister thecardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT janhaas thecardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT oliverjmuller thecardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT michaelboutros thecardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT matthiasnahrendorf thecardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT hugoakatus thecardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT stefanehardt thecardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT florianleuschner thecardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT ingmarsorenmeyer cardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT andreasjungmann cardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT christophdieterich cardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT minzhang cardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT felixlasitschka cardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT susannwerkmeister cardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT janhaas cardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT oliverjmuller cardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT michaelboutros cardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT matthiasnahrendorf cardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT hugoakatus cardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT stefanehardt cardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction AT florianleuschner cardiacmicroenvironmentusesnoncanonicalwntsignalingtoactivatemonocytesaftermyocardialinfarction |