Abstract
The heart hosts tissue resident macrophages which are capable of modulating cardiac inflammation and function by multiple mechanisms. At present, the consequences of phenotypic diversity in macrophages in the heart are incompletely understood. The contribution of cardiac M2-polarized macrophages to the resolution of inflammation and repair response following myocardial infarction remains to be fully defined. In this study, the role of M2 macrophages was investigated utilising a specific CSF-1 receptor signalling inhibition strategy to achieve their depletion. In mice, oral administration of GW2580, a CSF-1R kinase inhibitor, induced significant decreases in Gr1lo and F4/80hi monocyte populations in the circulation and the spleen. GW2580 administration also induced a significant depletion of M2 macrophages in the heart after 1 week treatment as well as a reduction of cardiac arginase1 and CD206 gene expression indicative of M2 macrophage activity. In a murine myocardial infarction model, reduced M2 macrophage content was associated with increased M1-related gene expression (IL-6 and IL-1β), and decreased M2-related gene expression (Arginase1 and CD206) in the heart of GW2580-treated animals versus vehicle-treated controls. M2 depletion was also associated with a loss in left ventricular contractile function, infarct enlargement, decreased collagen staining and increased inflammatory cell infiltration into the infarct zone, specifically neutrophils and M1 macrophages. Taken together, these data indicate that CSF-1R signalling is critical for maintaining cardiac tissue resident M2-polarized macrophage population, which is required for the resolution of inflammation post myocardial infarction and, in turn, for preservation of ventricular function.
Highlights
Cardiac tissue-resident macrophages, derived from circulating monocytes, exhibit an alternatively activated or M2 phenotype expressing cytoprotective factors and immune repressors such as IL-10 [1]
To induce significant depletion of M2 macrophages, MAFIA transgenic mice were treated with GW2580 (160 mg/kg, daily) or Vehicle for one week orally
Subtype analysis revealed that CSF-1R signaling inhibition depleted GFP+/Gr1lo (ÃÃ:p
Summary
Cardiac tissue-resident macrophages, derived from circulating monocytes, exhibit an alternatively activated or M2 phenotype expressing cytoprotective factors and immune repressors such as IL-10 [1]. Macrophage maturation from monocyte precursors is mainly driven by signaling through colony stimulating factor receptor 1 (CSF-1R) and its ligand CSF-1, which stimulates proliferation, differentiation, chemotaxis towards CSF-1 and survival of monocytes and macrophages. Binding of CSF-1 leads to autophosphorylation of receptor subunits and regulation of different downstream molecules, leading to the pleiotropic effect of CFS-1 signalling. CSF-1 promotes the differentiation towards M2 anti-inflammatory macrophages, which can be inhibited by TNF-α. TNF-α is released by neutrophils and M1 macrophages promoting a pro-inflammatory environment and can modulate macrophage plasticity
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