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Urokinase plasminogen activator induces pro-fibrotic/m2 phenotype in murine cardiac macrophages
Jessica Meznarich1, Laura Malchodi, Deri Helterline
1University of Washington School of Medicine, Division of Cardiology, Seattle, Washington, United States of America.
Objective:
Inflammation and fibrosis are intertwined in multiple disease processes. We have previously found that over-expression of urokinase plasminogen activator in macrophages induces spontaneous macrophage accumulation and fibrosis specific to the heart in mice. Understanding the relationship between inflammation and fibrosis in the heart is critical to developing therapies for diverse myocardial diseases. Therefore, we sought to determine if uPA induces changes in macrophage function that promote cardiac collagen accumulation.
Methods And Results:
We analyzed the effect of the uPA transgene on expression of pro-inflammatory (M1) and pro-fibrotic (M2) genes and proteins in hearts and isolated macrophages of uPA overexpressing mice. We found that although there was elevation of the pro-inflammatory cytokine IL-6 in hearts of transgenic mice, IL-6 is not a major effector of uPA induced cardiac fibrosis. However, uPA expressing bone marrow-derived macrophages are polarized to express M2 genes in response to IL-4 stimulation, and these M2 genes are upregulated in uPA expressing macrophages following migration to the heart. In addition, while uPA expressing macrophages express a transcriptional profile that is seen in tumor-associated macrophages, these macrophages promote collagen expression in cardiac but not embryonic fibroblasts.
Conclusions:
Urokinase plasminogen activator induces an M2/profibrotic phenotype in macrophages that is fully expressed after migration of macrophages into the heart. Understanding the mechanisms by which uPA modulates macrophage function may reveal insights into diverse pathologic processes.
Insights
Urokinase plasminogen activator (uPA) drives M2/profibrotic macrophage phenotypes, promoting cardiac fibrosis. This occurs after macrophages migrate to the heart, highlighting uPA
Area of Science:
- Cardiovascular Biology
- Immunology
- Fibrosis Research
Background:
- Inflammation and fibrosis are key drivers in various heart diseases.
- Previous studies linked urokinase plasminogen activator (uPA) overexpression in macrophages to cardiac fibrosis.
- Understanding the inflammation-fibrosis link is crucial for developing myocardial disease therapies.
Purpose of the Study:
- To investigate if uPA influences macrophage function, promoting cardiac collagen accumulation.
- To determine the role of uPA in macrophage polarization and its impact on cardiac fibrosis.
Main Methods:
- Analyzed gene and protein expression of M1 (pro-inflammatory) and M2 (pro-fibrotic) markers in uPA-overexpressing mice.
- Examined expression in both whole hearts and isolated macrophages.
- Assessed macrophage polarization in response to IL-4 stimulation and collagen expression in fibroblasts.
Main Results:
- Elevated Interleukin-6 (IL-6) in transgenic mouse hearts was not a primary driver of fibrosis.
- uPA-expressing macrophages polarized towards an M2 phenotype upon IL-4 stimulation.
- M2 gene upregulation occurred in uPA-expressing macrophages post-migration to the heart, promoting cardiac collagen deposition.
Conclusions:
- Urokinase plasminogen activator induces an M2/profibrotic phenotype in macrophages.
- This profibrotic phenotype is fully realized after macrophage migration into the cardiac tissue.
- Elucidating uPA's role in macrophage modulation offers insights into pathological processes.
