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* Istituto Clinico Humanitas, Rozzano, Italy;
Institute of General Pathology, University of Milan, Milan, Italy; and
Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
Comprehensive analysis of the gene expression profiles associated with human monocyte-to-macrophage differentiation and polarization toward M1 or M2 phenotypes led to the following main results: 1) M-CSF-driven monocyte-to-macrophage differentiation is associated with activation of cell cycle genes, substantiating the underestimated proliferation potential of monocytes. 2) M-CSF leads to expression of a substantial part of the M2 transcriptome, suggesting that under homeostatic conditions a default shift toward M2 occurs. 3) Modulation of genes involved in metabolic activities is a prominent feature of macrophage differentiation and polarization. 4) Lipid metabolism is a main category of modulated transcripts, with expected up-regulation of cyclo-oxygenase 2 in M1 cells and unexpected cyclo-oxygenase 1 up-regulation in M2 cells. 5) Each step is characterized by a different repertoire of G protein-coupled receptors, with five nucleotide receptors as novel M2-associated genes. 6) The chemokinome of polarized macrophages is profoundly diverse and new differentially expressed chemokines are reported. Thus, transcriptome profiling reveals novel molecules and signatures associated with human monocyte-to-macrophage differentiation and polarized activation which may represent candidate targets in pathophysiology.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Italian Association for Cancer Research, Ministero dell’Istruzione dell’Università e della Ricerca (Fondo Investimenti Ricerca di Base, Progetto di Rilevante Interesse Nazionale, and Consiglio Nazionale delle Ricerche funding), Fondo Interno per la Ricerca Scientifica e Tecnologica (FIRST Project), Ministero della Salute, Fondazione Cariplo (NOBEL Project), and the European Commission (Innochem Project, FP6-518167; Mugen Project, LSHG-CT-2005-005203). F.O.M. is a recipient of the International PhD program in Cellular and Molecular Biology fellowship from Vita-Salute San Raffaele University.
2 Address correspondence and reprint requests to Dr. Massimo Locati, Istituto Clinico Humanitas, Via Manzoni 56, I-20089 Rozzano, Italy. E-mail address: massimo.locati{at}humanitas.it
3 Abbreviations used in this paper: PCA, principal component analysis; GO, Gene Ontology; GPCR, G protein-coupled receptor; ALOX5, arachidonate 5-lipoxygenase; COX, cyclooxygenase; Mo, monocyte; M
, macrophage.
4 The online version of this article contains supplemental material.
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