The chemokine CXCL12 regulates monocyte-macrophage differentiation and RUNX3 expression

Abstract

Monocytes are versatile cells that can express different functional programs in response to microenvironmental signals. We show that primary blood monocytes secrete the CXCL12 chemokine, and express the CXCR4 and CXCR7 receptors, leading to an autocrine/paracrine loop that contribute to shape monocyte differentiation to a distinct type of macrophages, with an enhanced expression of CD4, CD14, and CD163, or dendritic cells, with a reduced functional ability to stimulate antigen-specific T-lymphocyte responses. The in vivo relevance of CXCL12 production by mononuclear phagocytes was studied in metastatic melanoma tissues by a thoroughly immunofluorescence phenotyping of CXCL12 high expressing cells, which were CD45 ؉ , coexpressed the macrophage antigens CD68, CD163, and CD209 and constituted the 60%-90% of tumor-associated macrophages. Microarray analysis of primary monocytes revealed that the vascular endothelial growth factor and the angiogenic chemokine CCL1 mRNA levels were up-regulated in response to CXCL12, leading to enhanced expression of both proteins. In addition, we found that CXCL12 autocrine/paracrine signaling down-regulates the expression of the transcription factor RUNX3 and contributes to maintain the longterm CD4 and CD14 expression in monocytes/macrophages. Together, these results suggest that autocrine CXCL12 production modulates differentiation of monocytes toward a distinct program with proangiogenic and immunosuppressive functions. (Blood. 2011;117(1): 88-97) IntroductionMonocytes are not fully differentiated cells, derived from the bone marrow, that circulate in blood during 1 to 3 days and enter peripheral tissues to give rise to a heterogeneous lineage of mononuclear phagocytes. Monocytes are highly recruited into foci of active inflammation, but they also enter into healthy tissues as part of the constitutive or steady-state trafficking to become resident tissue macrophages. 1 In response to inflammation or microbial products, such as the pro-Th1 stimuli interferon-␥ and granulocyte macrophage colony-stimulating factor (GM-CSF) or lipopolysaccharide (LPS), blood monocytes differentiate to inflammatory macrophages (M1) and dendritic cells (DCs). In contrast, in response to pro-Th2/anti-inflammatory stimuli , IL-10 and M-CSF) monocytes become anti-inflammatory macrophages (M2). 2 In vitro, human monocytes can differentiate into DCs in response to GM-CSF and IL-4 or into GM-CSFderived macrophages (M1), or M-CSF-driven macrophages (M2). In the tumor microenvironment, incoming monocytes are influenced by tumor-derived growth factors, especially M-CSF, IL-10, IL-6, and transforming growth factor-␤ (TGF-␤), which switch monocyte differentiation toward M2 macrophages rather than M1 or DCs. 3,4 Thus, monocytes are versatile cells that can express different functional programs in response to environmental signals.Blood monocytes are recruited into tissues in response to chemoattractants, most of which belong to the chemokine family. 5 Chemokines are small (8-14 kDa) secreted proteins that regulat...

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