CCL2 Shapes Macrophage Polarization by GM-CSF and M-CSF: Identification of CCL2/CCR2-Dependent Gene Expression Profile

Sierra‐Filardi, Elena; Nieto, Concha; Domínguez-Soto, Ángeles; Barroso, Rubén; Sánchez‐Mateos, Paloma; Puig‐Kröger, Amaya; López-Bravo, Marı́a; Joven, Jorge; Ardavı́n, Carlos; Rodrı́guez-Fernández, José Luis; Sánchez-Torres, Carmen; Mellado, Mario; Corbí, Ángel L.

doi:10.4049/jimmunol.1302821

Cited by 409 publications

(330 citation statements)

References 77 publications

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“…More recently, it was also found that CSF-1-differentiated macrophages obtained from human PBMC express and produce CCL2, while GM-CSF-differentiated macrophages express CCL2R. CD14 + TAM isolated from ascitic fluid of different types of cancer express CCL2 at an even higher extent that CSF-1-differentiated macrophages [102]. Taken together, the above-described results support further a protumoral activity of CSF-1R signaling.…”

Section: Pro-tumoral Activity Of Csf-1r Signaling In Tamsupporting

confidence: 72%

Colony-Stimulating Factor-1 Receptor in the Polarization of Macrophages: A Target for Turning Bad to Good Ones?

Rovida¹,

Sbarba²

2015

J Clin Cell Immunol

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Macrophages, which are found in all tissues, are an essential component of the innate immune system, and they play important roles in host defense, inflammation, autoimmune diseases as well as cancer. Functionally, macrophages are classified into two types: classically-activated M1 macrophages and alternatively-activated M2 macrophages. The M1 macrophages typically produce high levels of proinflammatory cytokines and chemokines, whereas M2 macrophages show an efficient phagocytic and scavenging activity. Because the phenotypes of polarized M1 and M2 macrophages can be induced, and reversed to some extent, by various signals, different phases of many diseases are associated with dynamic changes in the balance between M1 and M2 macrophages. The colony-stimulating factor 1 receptor (CSF-1R), a class III receptor tyrosine kinase, sustains the survival, proliferation and differentiation of monocytes and macrophages. Drugging CSF-1R may be the only way to target macrophages within a pathological context. However, CSF-1R-dependent signals may be either positive or detrimental depending on the disease and even on the phase of disease. The role of CSF-1R and its ligands, the colony-stimulating factor-1 and interleukin-34, in macrophages with respect to the pathogenesis of several inflammatory or neoplastic diseases has been reviewed previously. This review will focus specifically on evidences obtained about the role of CSF-1R in macrophage polarization in the context of physiological as well as pathological conditions including inflammation and cancer. The possibility to target CSF-1R, using the several inhibitors already available, for the treatment of inflammatory diseases as well as cancer will be also discussed.

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Section: Pro-tumoral Activity Of Csf-1r Signaling In Tamsupporting

confidence: 72%

Colony-Stimulating Factor-1 Receptor in the Polarization of Macrophages: A Target for Turning Bad to Good Ones?

Rovida¹,

Sbarba²

2015

J Clin Cell Immunol

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“…1C). As expected, the four Mf populations expressed the lineage-specific marker PU.1 (32) (Fig. 1E), whereas M14 and M16 exhibited higher levels of MAFB and HO-1 (molecules associated with the M-Mf phenotype) (32,33) than did GM14 and GM16 (Fig.…”

Section: Phenotypic and Functional Features Of Gm-and M-csf-derived Mmentioning

confidence: 73%

Atypical Activin A and IL-10 Production Impairs Human CD16+ Monocyte Differentiation into Anti-Inflammatory Macrophages

González-Domínguez

Domínguez-Soto

Nieto

et al. 2016

The Journal of Immunology

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Human CD14++CD16− and CD14+/loCD16+ monocyte subsets comprise 85 and 15% of blood monocytes, respectively, and are thought to represent distinct stages in the monocyte differentiation pathway. However, the differentiation fates of both monocyte subsets along the macrophage (Mϕ) lineage have not yet been elucidated. We have now evaluated the potential of CD14++ CD16− and CD16+ monocytes to differentiate and to be primed toward pro- or anti-inflammatory Mϕs upon culture with GM-CSF or M-CSF, respectively (subsequently referred to as GM14, M14, GM16, or M16). Whereas GM16 and GM14 were phenotypic and functionally analogous, M16 displayed a more proinflammatory profile than did M14. Transcriptomic analyses evidenced that genes associated with M-CSF–driven Mϕ differentiation (including FOLR2, IL10, IGF1, and SERPINB2) are underrepresented in M16 with respect to M14. The preferential proinflammatory skewing of M16 relative to M14 was found to be mediated by the secretion of activin A and the low levels of IL-10 produced by M16. In fact, activin A receptor blockade during the M-CSF–driven differentiation of CD16+ monocytes, or addition of IL-10–containing M14-conditioned medium, significantly enhanced their expression of anti-inflammatory–associated molecules while impairing their acquisition of proinflammatory-related markers. Thus, we propose that M-CSF drives CD14++CD16ˉ monocyte differentiation into bona fide anti-inflammatory Mϕs in a self-autonomous manner, whereas M-CSF–treated CD16+ monocytes generate Mϕs with a skewed proinflammatory profile by virtue of their high activin A expression unless additional anti-inflammatory stimuli such as IL-10 are provided.

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“…Previous reports have described differences in iron and folate metabolism between antitumoral/bactericidal and tumor-promoting macrophages (8) and between GM-MØ and M-MØ (9). A clear dichotomy exists in L-arginine metabolism between murine macrophages exposed to either LPS/IFN-g (high producers of NO via inducible NO synthase) or IL-4 (producers of ornithine and urea via Arginase-1).…”

mentioning

confidence: 99%

Reshaping of Human Macrophage Polarization through Modulation of Glucose Catabolic Pathways

Izquierdo

Cuevas

Fernández-Arroyo

et al. 2015

The Journal of Immunology

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Macrophages integrate information from the tissue microenvironment and adjust their effector functions according to the prevalent extracellular stimuli. Therefore, macrophages can acquire a variety of activation (polarization) states, and this functional plasticity allows the adequate initiation, regulation, and resolution of inflammatory responses. Modulation of the glucose metabolism contributes to the macrophage adaptation to the surrounding cytokine milieu, as exemplified by the distinct glucose catabolism of macrophages exposed to LPS/IFN-γ or IL-4. To dissect the acquisition of macrophage effector functions in the absence of activating cytokines, we assessed the bioenergetic profile of macrophages generated in the presence of GM-CSF (GM-MØ) or M-CSF (M-MØ), which do not release pro- or anti-inflammatory cytokines unless subjected to additional activating stimuli. Compared to M-MØ, GM-MØ displayed higher oxygen consumption rate and aerobic glycolysis (extracellular acidification rate [ECAR]), as well as higher expression of genes encoding glycolytic enzymes. However, M-MØ exhibited a significantly higher oxygen consumption rate/ECAR ratio. Surprisingly, whereas aerobic glycolysis positively regulated IL1B, TNF, and INHBA mRNA expression in both macrophage subtypes, mitochondrial respiration negatively affected IL6, IL1B, TNF, and CXCL10 mRNA expression in M-MØ. The physiological significance of these results became evident under low oxygen tensions, as hypoxia enhanced ECAR in M-MØ via HIF-1α and HIF-2α, increased expression of glycolytic enzymes and GM-MØ–specific genes, and diminished expression of M-MØ–associated genes. Therefore, our data indicate that GM-MØ and M-MØ display distinct bioenergetic profiles, and that hypoxia triggers a transcriptomic switch in macrophages by promoting a HIF-1α/HIF-2α-dependent increase in ECAR.

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CCL2 Shapes Macrophage Polarization by GM-CSF and M-CSF: Identification of CCL2/CCR2-Dependent Gene Expression Profile

Cited by 409 publications

References 77 publications

Colony-Stimulating Factor-1 Receptor in the Polarization of Macrophages: A Target for Turning Bad to Good Ones?

Colony-Stimulating Factor-1 Receptor in the Polarization of Macrophages: A Target for Turning Bad to Good Ones?

Atypical Activin A and IL-10 Production Impairs Human CD16+ Monocyte Differentiation into Anti-Inflammatory Macrophages

Reshaping of Human Macrophage Polarization through Modulation of Glucose Catabolic Pathways

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