Cellular reprogramming of human monocytes is regulated by time-dependent IL4 signalling and NCOR2 (original) (raw)
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Immunity, 2017
Human in vitro generated monocyte-derived dendritic cells (moDCs) and macrophages are used clinically, e.g., to induce immunity against cancer. However, their physiological counterparts, ontogeny, transcriptional regulation, and heterogeneity remains largely unknown, hampering their clinical use. High-dimensional techniques were used to elucidate transcriptional, phenotypic, and functional differences between human in vivo and in vitro generated mononuclear phagocytes to facilitate their full potential in the clinic. We demonstrate that monocytes differentiated by macrophage colony-stimulating factor (M-CSF) or granulocyte macrophage colony-stimulating factor (GM-CSF) resembled in vivo inflammatory macrophages, while moDCs resembled in vivo inflammatory DCs. Moreover, differentiated monocytes presented with profound transcriptomic, phenotypic, and functional differences. Monocytes integrated GM-CSF and IL-4 stimulation combinatorically and temporally, resulting in a mode- and time-d...
Journal of Leukocyte Biology, 2007
Macrophages and dendritic cells (DC) are APC, which regulate innate and adaptive immune responses. Macrophages function locally mainly, maintaining inflammatory responses in tissues, whereas DC take up microbes, mature, and migrate to local lymph nodes to present microbial antigens to naïve T cells to elicit microbe-specific immune responses. Blood monocytes can be differentiated in vitro to macrophages or DC by GM-CSF or GM-CSF ؉ IL-4, respectively. In the present study, we performed global gene expression analyses using Affymetrix HG-U133A Gene Chip oligonucleotide arrays during macrophage and DC differentiation. During the differentiation process, 340 and 350 genes were up-regulated, and 190 and 240 genes were down-regulated in macrophages and DC, respectively. There were also more that 200 genes, which were expressed differentially in fully differentiated macrophages and DC. Macrophage-specific genes include, e.g., CD14, CD163, C5R1, and Fc␥R1A, and several cell surface adhesion molecules, cytokine receptors, WNT5A and its receptor of the Frizzled family FZD2, fibronectin, and FcR1A were identified as DC-specific. Our results reveal significant differences in gene expression profiles between macrophages and DC, and these differences can partially explain the functional differences between these two important cell types. J. Leukoc. Biol. 82: 000 -000; 2007.
European Journal of Immunology, 2008
Myeloid dendritic cells (DC) and macrophages evolve from a common precursor. However, factors controlling monocyte differentiation toward DC or macrophages are poorly defined. We report that the surface density of the GM-CSF receptor (GM-CSFR) a subunit in human peripheral blood monocytes varies among donors. Although no correlation was found between the extent of GM-CSFR and monocyte differentiation into DC driven by GM-CSF and IL-4, GM-CSFR expression strongly influenced the generation of CD1a + dendritic-like cells in the absence of IL-4. CD1a + cells generated in the presence of GM-CSF express CD40, CD80, MHC class I and II, DC-SIGN, MR, CCR5, and partially retain CD14 expression. Interestingly, they spontaneously induce the expansion of CD4 + and CD8 + allogeneic T lymphocytes producing IFN-c, and migrate toward CCL4 and CCL19. Upon stimulation with TLR ligands, they acquire the phenotypic features of mature DC. In contrast, the allostimulatory capacity is not further increased upon LPS activation. However, by blocking LPS-induced IL-10, a higher T cell proliferative response and IL-12 production were observed. Interestingly, IL-23 secretion was not affected by endogenous IL-10. These results highlight the importance of GM-CSFR expression in monocytes for cytokine-induced DC generation and point to GM-CSF as a direct player in the generation of functionally distinct DC.
Journal of Allergy and Clinical Immunology, 2014
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GM-CSF differentiation of human monocytes stabilizes macrophage state via oxidative signaling
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Macrophages are central mediators of immunity that integrate diverse signals derived from differentiation cues, tissue location, and disease. Controlling macrophage state and function is an appealing therapeutic objective across many diseases including cancer, atherosclerosis, and tuberculosis. Despite the growing appreciation for the in vivo complexity of macrophage state, existing in vitro models of human monocyte-derived macrophages have used a limited number of individual perturbations to explore the complex phenotypic space that macrophages can occupy. Here, we leverage a tiered differentiation, activation, and stimulation strategy to generate libraries of in vitro monocyte-derived macrophages and examine the in vitro state space of macrophage function using high-dimensional technologies. Our tiered experimental approach further revealed a striking relationship between GM-CSF differentiation and IL-10 production. Cells that were differentiated with GM-CSF produced very low or u...
Constraints for monocyte-derived dendritic cell functions under inflammatory conditions
European Journal of Immunology, 2012
The activation of TLRs expressed by macrophages or DCs, in the long run, leads to persistently impaired functionality. TLR signals activate a wide range of negative feedback mechanisms; it is not known, however, which of these can lead to long-lasting tolerance for further stimulatory signals. In addition, it is not yet understood how the functionality of monocyte-derived DCs (MoDCs) is influenced in inflamed tissues by the continuous presence of stimulatory signals during their differentiation. Here we studied the role of a wide range of DC-inhibitory mechanisms in a simple and robust model of MoDC inactivation induced by early TLR signals during differentiation. We show that the activationinduced suppressor of cytokine signaling 1 (SOCS1), IL-10, STAT3, miR146a and CD150 (SLAM) molecules possessed short-term inhibitory effects on cytokine production but did not induce persistent DC inactivation. On the contrary, the LPS-induced IRAK-1 downregulation could alone lead to persistent MoDC inactivation. Studying cellular functions in line with the activation-induced negative feedback mechanisms, we show that early activation of developing MoDCs allowed only a transient cytokine production that was followed by the downregulation of effector functions and the preservation of a tissueresident non-migratory phenotype.
RNA sequencing and transcriptomal analysis of human monocyte to macrophage differentiation
Gene, 2013
Monocytes can be differentiated into macrophages in vivo and these cells play an important role in innate and adaptive immune responses. To reveal the global gene transcription change that occurs during monocyte to macrophage differentiation, we performed genome-wide RNA sequencing and analyses in human primary monocytes and monocyte-derived macrophages. We show that 1208 genes (with >twofold differences) were differentially expressed in macrophages compared with monocytes, including 800 upregulated and 408 downregulated genes. Gene ontology, pathway, and protein-protein interaction analyses indicated that the upregulated genes were related to macrophage functions in phagocytosis, metabolic processes, and cell cycle. The majority of downregulated genes comprised genes involved in the inflammatory response and locomotion. Genes encoding transcription regulatory factors, such as FOXO1, RUNX3, NF-κB1, and C/EBP δ, were highly expressed in monocytes and appeared to function in significant transcriptional repression, resulting in slight metabolic activity. Our transcriptome comparison between human monocytes and monocyte-derived macrophages using RNA sequencing revealed novel molecules and pathways associated with the differentiation process. These molecules and pathways may represent candidate targets involved in the pathophysiology of these important immune cells.
Mucosal Immunology, 2018
The tissue dendritic cell (DC) compartment is heterogeneous, and the ontogeny and functional specialization of human tissue conventional DC (cDC) subsets and their relationship with monocytes is unresolved. Here we identify monocyte-related CSF1R + Flt3antigen presenting cells (APCs) that constitute about half of the cells classically defined as SIRPα + DCs in the steady-state human small intestine. CSF1R + Flt3-APCs express calprotectin and very low levels of CD14, are transcriptionally related to monocytederived cells, and accumulate during inflammation. CSF1R + Flt3-APCs show typical macrophage characteristics functionally distinct from their Flt3 + cDC counterparts: under steady-state conditions they excel at antigen uptake, have a lower migratory potential, and are inefficient activators of naïve T cells. These results have important implications for the understanding of the ontogenetic and functional heterogeneity within human tissue DCs and their relation to the monocyte lineage.
Maturation of Human Monocyte-Derived Dendritic Cells Studied by Microarray Hybridization
Biochemical and Biophysical Research Communications, 2000
We compared the transcript profiles of human myeloid immature dendritic (IDC) cells and mature dendritic cells (MDC) by hybridization of cell-derived cDNA to DNA probes immobilized on microarrays. The microarrays contained probes for 4110 known genes. We report maturation-dependent changes in transcription of clusters of differentiation, cytokines, cytokine receptors, chemokines, chemokine receptors, neuropeptides, adhesion molecules, and other genes. We identified 1124 transcripts expressed in IDC and 1556 transcripts expressed in MDC. Maturation increased the levels of 291 transcripts twofold or more and reduced the levels of 78 transcripts to one-half or less than in IDC. We identified a concerted maturation-stage-dependent transcription of the variable chains of the members of the ␥-chain-cytokine receptor family IL-4R, IL-7R, and IL-15R. Also, we found the reversal of the ratio of transcripts for galectin-3 and galectin-9 upon maturation. We identified maturation-dependent changes in the levels of transcripts for numerous genes encoding proteins previously undetected in dendritic cells such as indoleamine 2,3-deoxygenase, Epstein-Barr virus induced protein 3 and kinesin-2. Moreover, MDC transcribed and translated insulin like growth factor-1 receptor, transforming growth factor ␣, and neuropeptide Y.
Transcriptional diversity during monocyte to macrophage differentiation
Immunology Letters, 2008
Monocytes recruited into tissues from peripheral blood differentiate into macrophages, which are critical in the pathogenesis of many diseases. There is limited data concerning the global changes in the expression of genes during monocyte to macrophage differentiation, and how the patterns of change identify the mechanism contributing to macrophage differentiation or function. Employing microarray technology, we examined the transcriptional profile of in vitro adherence-induced differentiation of primary human monocytes into macrophages. We found the significant up regulation of genes contributing to the functions of macrophages, including those regulating to immunity and defense; lipid, fatty acid and steroid metabolism; cell adhesion, carbohydrate metabolism; amino acid metabolism and endocytosis. In contrast, the vast majority of transcription factors affected were down regulated during monocyte to macrophage differentiation, suggesting that transcriptional repression may be important for the transition from monocytes to macrophages. However, a limited number of transcription factors were up regulated, among these was C/EBPα, which may contribute to differentiation by regulating down stream genes, which are a characteristic of differentiated macrophages. These observations suggest that examination of the transcriptional profile in monocytes and macrophages in patients may identify relevant therapeutic targets in diseases mediated by macrophages.