title: CXCL4-induced plaque macrophages can be specifically identified by co-expression of MMP7+S100A8+ in vitro and in vivo.
abstract: Macrophage heterogeneity in human atherosclerotic plaques has been recognized; however, markers for unequivocal identification of some subtypes are lacking. We found that the platelet chemokine CXCL4 induces a unique macrophage phenotype, which we proposed to call 'M4'. Here, we sought to identify suitable markers that identify M4 macrophages in vitro and in vivo. Using a stringent algorithm, we identified a set of potential markers from transcriptomic data derived from polarized macrophages. We specifically focused on matrix metalloproteinase (MMP)7 and S100A8, the co-expression of which has not been described in any macrophage type thus far. We found dose- and time-dependent MMP7 and S100A8 expression in M4 macrophages at the gene and protein levels. CXCL4-induced up-regulation of both MMP7 and S100A8 was curbed in the presence of heparin, which binds to CXCL4 and glycosaminoglycans, most likely representing the macrophage receptor for CXCL4. Immunofluorescence of post-mortem atherosclerotic coronary arteries identified CD68(+)MMP7(+), CD68(+)MMP7(-), CD68(+)S100A8(+) and CD68(+)S100A8(-) macrophages. A small proportion of MMP7(+)S100A8(+) macrophages most likely represent M4 macrophages. In summary, we have identified co-expression of MMP7 and S100A8 to be a marker combination exclusively found in M4 macrophages. This finding may allow further dissection of the role of M4 macrophages in atherosclerosis and other pathologic conditions.
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Erbel
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Tyka
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Helmes
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Mohmmadreza
authors.initials: M
authors.lastname: Akhavanpoor
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Rupp
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Domschke
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Linden
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Antonia
authors.initials: A
authors.lastname: Wolf
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Doesch
authors.affiliation: Department of Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Lasitschka
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany DZHK (German Centre for Cardiovascular Research), Heidelberg, Germany.
authors.forename: Hugo A
authors.initials: HA
authors.lastname: Katus
authors.affiliation: Department of Cardiology, University of Heidelberg, Heidelberg, Germany christian.gleissner@med.uni-heidelberg.de.
authors.forename: Christian A
authors.initials: CA
authors.lastname: Gleissner
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D001792:Blood Platelets / Q000276:immunology*; D040501:Calgranulin A / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000276:immunology; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism*; D058226:Plaque, Atherosclerotic / Q000175:diagnosis / Q000276:immunology*; D010978:Platelet Factor 4 / Q000276:immunology; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D040501:Calgranulin A; D010978:Platelet Factor 4; D016173:Macrophage Colony-Stimulating Factor; D020783:Matrix Metalloproteinase 7
keywords: Atherosclerosis; cell differentiation; chemokines; inflammation; macrophages