M-CSF favors the generation of folate receptor β-positive (FRβ⁺), IL-10-producing, immunosuppressive, M2-polarized macrophages [M2 (M-CSF)], whereas GM-CSF promotes a proinflammatory, M1-polarized phenotype [M1 (GM-CSF)]. In the present study, we found that activin A was preferentially released by M1 (GM-CSF) macrophages, impaired the acquisition of FRβ and other M2 (M-CSF)-specific markers, down-modulated the LPS-induced release of IL-10, and mediated the tumor cell growth-inhibitory activity of M1 (GM-CSF) macrophages, in which Smad2/3 is constitutively phosphorylated. The contribution of activin A to M1 (GM-CSF) macrophage polarization was evidenced by the capacity of a blocking anti-activin A antibody to reduce M1 (GM-CSF) polarization markers expression while enhancing FRβ and other M2 (M-CSF) markers mRNA levels. Moreover, an inhibitor of activin receptor-like kinase 4/5/7 (ALK4/5/7 or SB431542) promoted M2 (M-CSF) marker expression but limited the acquisition of M1 (GM-CSF) polarization markers, suggesting a role for Smad2/3 activation in macrophage polarization. In agreement with these results, expression of activin A and M2 (M-CSF)-specific markers was oppositely regulated by tumor ascites. Therefore, activin A contributes to the proinflammatory macrophage polarization triggered by GM-CSF and limits the acquisition of the anti-inflammatory phenotype in a Smad2-dependent manner. Our results demonstrate that activin A-initiated Smad signaling skews macrophage polarization toward the acquisition of a proinflammatory phenotype.

Here we show that scavenger receptor class B type I is present in the small-intestine brush border membrane where it facilitates the uptake of dietary cholesterol from either bile salt micelles or phospholipid vesicles. This receptor can also function as a port for several additional classes of lipids, including cholesteryl esters, triacylglycerols, and phospholipids. It is the first receptor demonstrated to be involved in the absorption of dietary lipids in the intestine. In liver and steroidogenic tissues, the physiological ligand of this receptor is high-density lipoprotein. We show that binding of high-density lipoprotein and apolipoprotein A-I to the brush border membrane-resident receptor inhibits uptake of cholesterol (sterol) into the brush border membrane from lipid donor particles. This finding lends further support to the conclusion that scavenger receptor BI catalyzes intestinal cholesterol uptake. Our findings suggest new therapeutic approaches for limiting the absorption of dietary cholesterol and reducing hypercholesterolemia and the risk of atherosclerosis.

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...