Dendritic Cell-Specific ICAM-3–Grabbing Nonintegrin Expression on M2-Polarized and Tumor-Associated Macrophages Is Macrophage-CSF Dependent and Enhanced by Tumor-Derived IL-6 and IL-10

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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“…GM14 and GM16 displayed a similar phenotype that concurred with that previously reported (16,29,(34)(35)(36) (Fig. 2A).…”

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

confidence: 91%

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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“…The correlation between PHD3 and macrophage M1 polarization is further supported by the restriction of PHD3 expression to a TAM subset that exhibits a low level of M2 polarization-associated markers and for which location differed from that of M2-polarized macrophages (highly positive for CD163 and FRb). Based on the pro-M2 polarization ability of tumor-conditioned media (46), it seems reasonable to assume that PHD3 + macrophages would give rise to FRb + TAM under the influence of tumor-derived factors like M-CSF. Regardless of the ontogenic relationships between both TAM subsets, the appearance of two subsets of CD68 + CD163…”

Section: Discussionmentioning

confidence: 99%

The Prolyl Hydroxylase PHD3 Identifies Proinflammatory Macrophages and Its Expression Is Regulated by Activin A

Escribese

Sierra‐Filardi

Nieto

et al. 2012

The Journal of Immunology

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Modulation of macrophage polarization underlies the onset and resolution of inflammatory processes, with polarization-specific molecules being actively sought as potential diagnostic and therapeutic tools. Based on their cytokine profile upon exposure to pathogenic stimuli, human monocyte-derived macrophages generated in the presence of GM-CSF or M-CSF are considered as proinflammatory (M1) or anti-inflammatory (M2) macrophages, respectively. We report in this study that the prolyl hydroxylase PHD3-encoding EGLN3 gene is specifically expressed by in vitro-generated proinflammatory M1(GM-CSF) human macrophages at the mRNA and protein level. Immunohistochemical analysis revealed the expression of PHD3 in CD163+ lung macrophages under basal homeostatic conditions, whereas PHD3+ macrophages were abundantly found in tissues undergoing inflammatory responses (e.g., Crohn’s disease and ulcerative colitis) and in tumors. In the case of melanoma, PHD3 expression marked a subset of tumor-associated macrophages that exhibit a weak (e.g., CD163) or absent (e.g., FOLR2) expression of typical M2-polarization markers. EGLN3 gene expression in proinflammatory M1(GM-CSF) macrophages was found to be activin A dependent and could be prevented in the presence of an anti-activin A-blocking Ab or inhibitors of activin receptor-like kinase receptors. Moreover, EGLN3 gene expression was upregulated in response to hypoxia only in M2(M-CSF) macrophages, and the hypoxia-mediated upregulation of EGLN3 expression was significantly impaired by activin A neutralization. These results indicate that EGLN3 gene expression in macrophages is dependent on activin A both under basal and hypoxic conditions and that the expression of the EGLN3-encoded PHD3 prolyl hydroxylase identifies proinflammatory macrophages in vivo and in vitro.

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“…As detected by confocal microscopy, M0 cells expressed the Folate receptor β (FRβ), stress-responsive heme-detoxification enzyme Heme Oxygenase-1 (HO-1), and CD209 (DC-SIGN), whose densities were strongly upregulated upon M2 polarization [14][15][16]. As shown in Supporting Information Fig.…”

Section: Membrane-bound Il-18 Is Selectively Expressed By M0 and M2 Mmentioning

confidence: 98%

M‐CSF induces the expression of a membrane‐bound form of IL‐18 in a subset of human monocytes differentiating in vitro toward macrophages

et al. 2012

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IL-18 is a proinflammatory cytokine belonging to the "IL-1 family" that has been shown to play a prominent role in the induction of type 1 immune responses. Here, we show that M-CSF induces the expression of a membrane-bound form of IL-18 (mIL-18) in a subset of human blood monocytes differentiating toward macrophages. While monocytes, DC, and GM-CSF-treated monocytes did not express mIL-18, its expression was detected in ap- IntroductionMacrophages produce IL-1 (IL-1α and IL-1β) and IL-18, proinflammatory cytokines that have been generally assigned to a larger Correspondence: Dr. Cristina Bottino e-mail: Cristina.Bottino@unige.it group of cytokines termed "IL-1 family" since they present related receptor structures and utilize similar signal transduction * These authors contributed equally to this study.C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2012. 42: 1618-1626 Innate immunity 1619 pathways [1,2]. IL-1α is synthesized as pro-IL-1α, a biologically active precursor that is constitutively present in cells and can be cleaved into a mature cytokine by calpain, a membrane-bound cysteine protease. IL-1α is not readily secreted by cells and remains either bound to plasma membrane [3] or inside the cells where it acts as an autocrine growth factor. IL-1β, the prototype of primary proinflammatory cytokines is not present in cells under steady state conditions. Its production is highly regulated and requires a first signal-inducing de novo transcription of the gene and accumulation of the inactive precursor cytokine (pro-IL-1β) and a second signal-driving inflammasome assembly [4] and activation of caspase-1 (also known as IL-1β-converting enzyme, ICE), which converts pro-IL-1β into the IL-1β bioactive mature cytokine. These signals are provided by pathogen-associated molecular patterns (PAMPs) that act through specific receptors such as Toll-like receptors (TLRs), cytokines such as IL-33, IL-1β itself, and IL-1α, which is released passively upon cell injury, danger-associated molecular patterns (DAMPs) such as urate crystals or pathogenic dusts and extracellular ATP, which after binding to P2 receptors (P2R) induces a rapid exit of potassium from the cell. Interestingly, also a caspase-1 independent type of IL-1β activation has been described. Thus, in different models of sterile inflammation, macrophages and monocytes would be able to release pro-IL-1β that is cleaved by proteinase-3 produced by neutrophils [1,5]. IL-18 originally identified as an IFN-γ-inducing factor (IGIF), has been shown to play a prominent role in the induction of type 1 immune responses [1,6,7]. Although belonging to the same cytokine family, IL-18 and IL-1β display both similarities and important differences [1,2]. Similar to IL-1β, IL-18 is synthesized as a biologically inactive precursor peptide (pro-IL-18) that is subsequently cleaved by caspase-1. Unlike IL-1β, however, PAMPs such as LPS while inducing IL-18 release have little impact on IL-18 gene transcription [2].Monocytes are a considerable r...

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Dendritic Cell-Specific ICAM-3–Grabbing Nonintegrin Expression on M2-Polarized and Tumor-Associated Macrophages Is Macrophage-CSF Dependent and Enhanced by Tumor-Derived IL-6 and IL-10

Cited by 123 publications

References 51 publications

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

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

The Prolyl Hydroxylase PHD3 Identifies Proinflammatory Macrophages and Its Expression Is Regulated by Activin A

M‐CSF induces the expression of a membrane‐bound form of IL‐18 in a subset of human monocytes differentiating in vitro toward macrophages

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