Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction
- Centro Nacional de Investigaciones Cardiovasculares, Spain
- Vall d'Hebron University Hospital and Research Institute, Spain
- Centro de Investigaciones Biológicas (CIB-CSIC), Spain
Abstract
Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. Here, we demonstrated that cardiac Mφs increased expression of Mmp14 (MT1-MMP) 7 days post-MI. We selectively inactivated the Mmp14 gene in Mφs using a genetic strategy (Mmp14f/f:Lyz2-Cre). This conditional KO (MAC-Mmp14 KO) resulted in attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in Mφs, leading to paracrine SMAD2-mediated signaling in endothelial cells (ECs) and endothelial-to-mesenchymal transition (EndMT). Post-MI MAC-Mmp14 KO hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and Mmp14-deficient Mφs showed a reduced ability to induce EndMT in co-cultures with ECs. Our results indicate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify Mφ MT1-MMP as a key regulator of this process.
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 all the figures.
Article and author information
Author details
Laura Alonso-Herranz
Funding
Spanish Ministry of Science, Innovation and Universities (SAF2017-90604-REDT-NurCaMein)
- Mercedes Ricote
Spanish Ministry of Science, Innovation and Universities (RTI2018-095928-BI00)
- Mercedes Ricote
Spanish Ministry of Science, Innovation and Universities (SAF2017-83229-R)
- Alicia G Arroyo
Comunidad de Madrid (MOIR-B2017/BMD-3684)
- Alicia G Arroyo
La Marato TV3 Foundation
- David García-Dorado
- Alicia G Arroyo
- Mercedes Ricote
Fundacion La Caixa
- Laura Alonso-Herranz
- Álvaro Sahún-Español
La Residencia de Estudiantes
- Álvaro Sahún-Español
FORD-Spain and Apadrina La Ciencia
- Álvaro Sahún-Español
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 procedures were conducted in accordance with EU Directive 86/609/EEC and approved by the Animal Subjects Committee of the Instituto de Salud Carlos III (Madrid, Spain) and Madrid Community Organs in the PROEX 188/26. All surgery was performed under anesthesia with sevoflurane (5% for induction, 2%-3% for maintenance) and buprenorphine (0.01 mg/kg, Buprex, Merck & Co. Inc) was given for pain relief.
Copyright
© 2020, Alonso-Herranz 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.
Metrics
-
- 3,406
- views
-
- 554
- downloads
-
- 56
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Macrophages promote endothelial-to-mesenchymal transition via MT1-MMP/TGFβ1 after myocardial infarction
eLife 9:e57920.
https://doi.org/10.7554/eLife.57920
Further reading
-
- Cell Biology
- Immunology and Inflammation
Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
Pseudomonas aeruginosa (PA) is an opportunistic, frequently multidrug-resistant pathogen that can cause severe infections in hospitalized patients. Antibodies against the PA virulence factor, PcrV, protect from death and disease in a variety of animal models. However, clinical trials of PcrV-binding antibody-based products have thus far failed to demonstrate benefit. Prior candidates were derivations of antibodies identified using protein-immunized animal systems and required extensive engineering to optimize binding and/or reduce immunogenicity. Of note, PA infections are common in people with cystic fibrosis (pwCF), who are generally believed to mount normal adaptive immune responses. Here, we utilized a tetramer reagent to detect and isolate PcrV-specific B cells in pwCF and, via single-cell sorting and paired-chain sequencing, identified the B cell receptor (BCR) variable region sequences that confer PcrV-specificity. We derived multiple high affinity anti-PcrV monoclonal antibodies (mAbs) from PcrV-specific B cells across three donors, including mAbs that exhibit potent anti-PA activity in a murine pneumonia model. This robust strategy for mAb discovery expands what is known about PA-specific B cells in pwCF and yields novel mAbs with potential for future clinical use.
