High-Resolution Transcriptome of Human Macrophages

Beyer, Marc; Mallmann, Michael R.; Xue, Jia; Staratschek‐Jox, Andrea; Vorholt, Daniela; Krebs, Wolfgang; Sommer, Daniel; Sander, Jil; Mertens, Claudia; Niño-Castro, Andrea; Schmidt, Susanne V.; Schultze, Joachim L.

doi:10.1371/journal.pone.0045466

Cited by 247 publications

(260 citation statements)

References 47 publications

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“…Flow cytometric analysis revealed increased macrophage manose receptor (MMR) expression on the surface of BALB/c macrophages BMMs compared with C57BL/6 macrophages ( Figure 8E), which is consistent with previously published transcriptional profiling data (35,38). To test whether the differential uptake of particles by BAL-B/c and C57BL/6 macrophages is MMR dependent, we treated the BMMs with the competitive MMR inhibitor mannan prior to the addition of particles.…”

Section: Figuresupporting

confidence: 88%

“…Cells were cultured with 25 ng/ml IL-4 (eBioscience) for M2 stimulation. Human macrophages were generated using a previously published protocol (38). Briefly, peripheral blood monocytes were collected from 2 healthy male volunteers, then cells were plated on 15-cm dishes in DMEM supplemented with 10% FBS, L-glutamine, penicillin-streptomycin, and 100 ng/ml human M-CSF (eBioscience) for 7 days.…”

Section: Cell Culture Reagentsmentioning

confidence: 99%

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Nanoparticle clearance is governed by Th1/Th2 immunity and strain background

Jones¹,

Roberts²,

Robbins³

et al. 2013

J. Clin. Invest.

174

164

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Extended circulation of nanoparticles in blood is essential for most clinical applications. Nanoparticles are rapidly cleared by cells of the mononuclear phagocyte system (MPS). Approaches such as grafting polyethylene glycol onto particles (PEGylation) extend circulation times; however, these particles are still cleared, and the processes involved in this clearance remain poorly understood. Here, we present an intravital microscopybased assay for the quantification of nanoparticle clearance, allowing us to determine the effect of mouse strain and immune system function on particle clearance. We demonstrate that mouse strains that are prone to Th1 immune responses clear nanoparticles at a slower rate than Th2-prone mice. Using depletion strategies, we show that both granulocytes and macrophages participate in the enhanced clearance observed in Th2-prone mice. Macrophages isolated from Th1 strains took up fewer particles in vitro than macrophages from Th2 strains. Treating macrophages from Th1 strains with cytokines to differentiate them into M2 macrophages increased the amount of particle uptake. Conversely, treating macrophages from Th2 strains with cytokines to differentiate them into M1 macrophages decreased their particle uptake. Moreover, these results were confirmed in human monocyte-derived macrophages, suggesting that global immune regulation has a significant impact on nanoparticle clearance in humans. IntroductionThe potential clinical applications of nanoparticles and nanoformulations have been investigated for more than 30 years. Nanoparticle approaches have the potential to revolutionize drug delivery by allowing for the encapsulation of drugs with poor solubility or stability in a stable carrier particle. In addition, targeting nanoparticles to specific pathological sites may allow an increased effective dose of drug at the needed site, while decreasing systemic drug exposure, and therefore side effects. However, to date, only 2 nanoformulations for cancer treatment have been approved for clinical use (liposomal doxorubicin [Doxil] and protein-bound paclitaxel [Abraxane]) (1-3). One major obstacle for the use of nanoparticles in vivo is rapid clearance by the cells of the reticuloendothelial system (RES)/mononuclear phagocyte system (MPS) (4-7). In addition to rapid clearance, variable activity of the MPS among patients leads to widely variable pharmacokinetics of nanoformulations in the clinic, reducing the efficacy of both approved and future experimental nanoformulations (8).

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Section: Figuresupporting

confidence: 88%

Section: Cell Culture Reagentsmentioning

confidence: 99%

Nanoparticle clearance is governed by Th1/Th2 immunity and strain background

Jones¹,

Roberts²,

Robbins³

et al. 2013

J. Clin. Invest.

174

164

View full text Add to dashboard Cite

show abstract

“…Interestingly, a recent study analyzing RNA-seq-based high-resolution transcriptome data identified both c-MYC and p53 as major hubs in the human M2 macrophage network. 12 We propose that c-MYC has a key role in the response of M2 macrophages to p53 activation.…”

Section: Resultsmentioning

confidence: 90%

A unique role for p53 in the regulation of M2 macrophage polarization

Li¹,

et al. 2014

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P53 is critically important in preventing oncogenesis but its role in inflammation in general and in the function of inflammatory macrophages in particular is not clear. Here, we show that bone marrow-derived macrophages exhibit endogenous p53 activity, which is increased when macrophages are polarized to the M2 (alternatively activated macrophage) subtype. This leads to reduced expression of M2 genes. Nutlin-3a, which destabilizes the p53/MDM2 (mouse double minute 2 homolog) complex, promotes p53 activation and further downregulates M2 gene expression. In contrast, increased expression of M2 genes was apparent in M2-polarized macrophages from p53-deficient and p53 mutant mice. Furthermore, we show, in mice, that p53 also regulates M2 polarization in peritoneal macrophages from interleukin-4-challenged animals and that nutlin-3a retards the development of tolerance to Escherichia coli lipopolysaccharide. P53 acts via transcriptional repression of expression of c-Myc (v-myc avian myelocytomatosis viral oncogene homolog) gene by directly associating with its promoter. These data establish a role for the p53/MDM2/c-MYC axis as a physiological 'brake' to the M2 polarization process. This work reveals a hitherto unknown role for p53 in macrophages, provides further insight into the complexities of macrophage plasticity and raises the possibility that p53-activating drugs, many of which are currently being trialled clinically, may have unforeseen effects on macrophage function. Macrophages have key roles in the response to stress, injury, infection and inflammation. The M1 (classically activated macrophages) are induced by lipopolysaccharide (LPS) and cytokines such as interferon-γ (IFNγ) and characterized by the expression of a wide range of proinflammatory genes. M2 (alternatively activated macrophages) are induced by T helper type 2 (Th2) cytokines such as interleukin-4 (IL4) and IL13 and express high levels of anti-inflammatory and tissue repair marker genes. M2 macrophages perform immunoregulatory functions including defense against infection, promotion of angiogenesis and wound healing. 1 Macrophages exist on a continuum between M1 and M2 subtypes undergoing dynamic changes between these different functional states depending on changes in their microenvironment. This 'plasticity' involves extensive changes in macrophage gene sets and provides the potential to develop drugs to manipulate the macrophage subtype. 2 As such, macrophage polarization, and its molecular basis, has been vigorously researched in recent years.P53 has a crucial role in cancer by controlling the expression of genes involved in apoptosis, cell cycle arrest, metabolism and DNA repair. 3 While inflammation is increasingly recognized as a factor in determining the predisposition to cancer, 4 the role of p53 in inflammation is not clear. Macrophages from p53 − / − mice produce increased quantities of proinflammatory cytokines in response to LPS, 5 while peritoneal macrophage count and susceptibility to lethal septic shock are increased in p53 − ...

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“…However, it is known that CD93 (C1qRp) is a transmembrane receptor regulating phagocytosis and cell adhesion and is present on cells of the myeloid lineage (45). CD93 expression is increased with monocyte differentiation and macrophage activation (46,47). Targeting of Cd93 mRNA by miR-29 could promote commitment to osteoclastogenesis, preventing monocytic differentiation.…”

Section: Discussionmentioning

confidence: 99%

miR-29 Promotes Murine Osteoclastogenesis by Regulating Osteoclast Commitment and Migration

Franceschetti

Kessler

Lee

et al. 2013

Journal of Biological Chemistry

111

110

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Background: miR-29 is a positive regulator of osteoblastogenesis, but its role in osteoclastogenesis is undefined. Results: Expression of all miR-29 family members increased during osteoclastic differentiation. miR-29 knockdown impaired migration, osteoclast commitment, and formation. Six novel miR-29 targets were identified. Conclusion: miR-29 promotes osteoclastogenesis. Significance: These data expand our understanding of osteoclastogenesis, providing insight into miR-29 function in hematopoietic cells and other lineages.

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High-Resolution Transcriptome of Human Macrophages

Cited by 247 publications

References 47 publications

Nanoparticle clearance is governed by Th1/Th2 immunity and strain background

Nanoparticle clearance is governed by Th1/Th2 immunity and strain background

A unique role for p53 in the regulation of M2 macrophage polarization

miR-29 Promotes Murine Osteoclastogenesis by Regulating Osteoclast Commitment and Migration

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