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.

Genome Wide Association Study Identifies 20 Novel Promising Genes Associated with Milk Fatty Acid Traits in Chinese Holstein

“…The top one significant SNP for C14:0 is within the carboxypeptidase M ( CPM ) gene. Up-regulation of CPM in macrophages (MAs) is associated with increased lipid uptake [41] and the highest expression of CPM was detected in human adipocyte cell [42] . The SNP associated with C18:1n9c, SFA, UFA and SFA/UFA is 0.77 Mbp away from the oxysterol binding protein-like 8 ( OSBPL8 ) gene which encodes a member of the oxysterol-binding protein (OSBP) family, a group of intracellular lipid receptors.…”

Mapping of Carboxypeptidase M in Normal Human Kidney and Renal Cell Carcinoma

“…Indubitably, CPM represents an excellent marker of active, foamy macrophages in RCC tissue and is a part of the tumoral inflammatory environment. Tsakiris et al (2012) very recently described a consistent expression of CPM in lipid-laden tissue macrophages, including foamy macrophages of early atherosclerotic plaques, and TAMs in invasive ductal carcinoma and seminoma when related to cell destruction and subsequent lipid uptake. Comparable to our observations, CD68 (and CD163) antibodies appeared to stain other tissue macrophages besides the lipid-laden ones as compared with the CPM antibodies (Tsakiris et al 2012).…”

“…EGFR overexpression has been reported for numerous other carcinoma types with squamous cell histology, including head and neck cancer and non-small cell lung cancer that are currently treated with EGFR antagonists among other medication (Kamath and Buolamwini 2006;Ciardiello and Tortora 2008). Analogously to the study by Tsakiris et al (2012) in lung adenocarcinoma, coexpression of CPM and EGFR was analyzed in RCC. Cluster analysis of CPM and EGFR H-scores revealed coexistence only in one tumor group (i.e., papillary RCC).…”

Predictive value of serum bradykinin and desArg9-bradykinin levels for chemotherapeutic responses in active tuberculosis patients: A retrospective case series

“…CPM activity, which plays an important role in BK production, is expressed on the plasma membrane of a broad variety of cells and tissues, including blood vessels, pneumocytes, macrophages and granulomas [24], preferentially induced in epithelioid cell (EPC) clusters of all granuloma types [40] and can be released from plasma membranes by bacterial phosphatidylinositol-specific phospholipase C activity [30]. Moreover, upregulation of CPM correlates to increasing endogenous levels of DABK and B1R agonists in bacterial lipopolysaccharide-induced inflammatory responses [29], while the DABK receptor B1R can be induced on cellular components of granulomas, including epithelial cells, macrophages, fibroblasts and lymphocytes [15,41,42].…”