title: Systemic and Cardiac Depletion of M2 Macrophage through CSF-1R Signaling Inhibition Alters Cardiac Function Post Myocardial Infarction.
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.
authors.affiliation: Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, College Road, Cork, Ireland.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Leblond
authors.affiliation: Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, College Road, Cork, Ireland.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Klinkert
authors.affiliation: Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, College Road, Cork, Ireland.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Martin
authors.affiliation: Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, College Road, Cork, Ireland.
authors.forename: Elizebeth C
authors.initials: EC
authors.lastname: Turner
authors.affiliation: Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, College Road, Cork, Ireland.
authors.forename: Arun H
authors.initials: AH
authors.lastname: Kumar
authors.affiliation: Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, College Road, Cork, Ireland.
authors.forename: Tara
authors.initials: T
authors.lastname: Browne
authors.affiliation: Centre for Research in Vascular Biology (CRVB), Biosciences Institute, University College Cork, College Road, Cork, Ireland.
authors.forename: Noel M
authors.initials: NM
authors.lastname: Caplice
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D001119:Arginase / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C506269:5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine; D000840:Anisoles; C000604004:Csf1r protein, mouse; C587672:IL1B protein, mouse; D053583:Interleukin-1beta; D015850:Interleukin-6; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D011743:Pyrimidines; D011956:Receptors, Cell Surface; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; C544448:Arg1 protein, mouse; D001119:Arginase