title: Carboxypeptidase-M is regulated by lipids and CSFs in macrophages and dendritic cells and expressed selectively in tissue granulomas and foam cells.
abstract: Granulomatous inflammations, characterized by the presence of activated macrophages (MAs) forming epithelioid cell (EPC) clusters, are usually easy to recognize. However, in ambiguous cases the use of a MA marker that expresses selectively in EPCs may be needed. Here, we report that carboxypeptidase-M (CPM), a MA-differentiation marker, is preferentially induced in EPCs of all granuloma types studied, but not in resting MAs. As CPM is not expressed constitutively in MAs, this allows utilization of CPM-immunohistochemistry in diagnostics of minute granuloma detection when dense non-granulomatous MAs are also present. Despite this rule, hardly any detectable CPM was found in advanced/active tubercle caseous disease, albeit in early tuberculosis granuloma, MAs still expressed CPM. Indeed, in vitro both the CPM-protein and -mRNA became downregulated when MAs were infected with live mycobacteria. In vitro, MA-CPM transcript is neither induced remarkably by interferon-γ, known to cause classical MA activation, nor by IL-4, an alternative MA activator. Instead, CPM is selectively expressed in lipid-laden MAs, including the foam cells of atherosclerotic plaques, xanthomatous lesions and lipid pneumonias. By using serum, rich in lipids, and low-density lipoprotein (LDL) or VLDL, CPM upregulation could be reproduced in vitro in monocyte-derived MAs both at transcriptional and protein levels, and the increase is repressed under lipid-depleted conditions. The microarray analyses support the notion that CPM induction correlates with a robust progressive increase in CPM gene expression during monocyte to MA maturation and dendritic cell (DC) differentiation mediated by granulocyte-MA-colony-stimulating factor+IL-4. M-CSF alone also induced CPM. These results collectively indicate that CPM upregulation in MAs is preferentially associated with increased lipid uptake, and exposure to CSF, features of EPCs, also. Therefore, CPM-immunohistochemistry is useful for granuloma and foam MA detections in tissue sections. Furthermore, the present data offer CPM for the first time to be a novel marker and cellular player in lipid uptake and/or metabolism of MAs by promoting foam cell formation.
authors.affiliation: Department of Pathology, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Tsakiris
authors.forename: Daniel
authors.initials: D
authors.lastname: Torocsik
authors.forename: Adrienn
authors.initials: A
authors.lastname: Gyongyosi
authors.forename: Aniko
authors.initials: A
authors.lastname: Dozsa
authors.forename: Istvan
authors.initials: I
authors.lastname: Szatmari
authors.forename: Attila
authors.initials: A
authors.lastname: Szanto
authors.forename: Gyorgyike
authors.initials: G
authors.lastname: Soos
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Nemes
authors.forename: Laszlo
authors.initials: L
authors.lastname: Igali
authors.forename: Ildiko
authors.initials: I
authors.lastname: Marton
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Takats
authors.forename: Laszlo
authors.initials: L
authors.lastname: Nagy
authors.forename: Balazs
authors.initials: B
authors.lastname: Dezso
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D015622:Epithelioid Cells / Q000201:enzymology*; D005487:Foam Cells / Q000201:enzymology*; D058851:GPI-Linked Proteins / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006099:Granuloma / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D015847:Interleukin-4 / Q000378:metabolism; D050356:Lipid Metabolism; D008666:Metalloendopeptidases / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; D058851:GPI-Linked Proteins; C508598:IL4 protein, human; D012333:RNA, Messenger; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C058479:carboxypeptidase M; D008666:Metalloendopeptidases