Reprogramming of macrophages — new opportunities for therapeutic targeting

Schultze, Joachim L.

doi:10.1016/j.coph.2015.09.007

Cited by 63 publications

(44 citation statements)

References 68 publications

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“…36 Our results provide a cautionary note to this approach, indicating that constitutive apoptosis in the tumor or apoptosis induced by repolarized, cytotoxic TAMs or by combination radiation or chemotherapy could militate against therapeutic success by contributing to what has been aptly termed ‘a misdirected tissue repair response'. 2 Further studies are required to identify the mechanisms responsible for the reprogramming of cytotoxic TAMs by apoptotic tumor cells as these could provide critical therapeutic targets.…”

Section: Discussionmentioning

confidence: 90%

Modulation of macrophage antitumor potential by apoptotic lymphoma cells

et al. 2017

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In aggressive non-Hodgkin's lymphoma (NHL), constitutive apoptosis of a proportion of the tumor cell population can promote net tumor growth. This is associated with the accumulation of tumor-associated macrophages (TAMs) that clear apoptotic cells and exhibit pro-oncogenic transcriptional activation profiles characteristic of reparatory, anti-inflammatory and angiogenic programs. Here we consider further the activation status of these TAMs. We compare their transcriptomic profile with that of a range of other macrophage types from various tissues noting especially their expression of classically activated (IFN-γ and LPS) gene clusters – typically antitumor – in addition to their previously described protumor phenotype. To understand the impact of apoptotic cells on the macrophage activation state, we cocultured apoptotic lymphoma cells with classically activated macrophages (M(IFN-γ/LPS), also known as M1, macrophages). Although untreated and M(IFN-γ/LPS) macrophages were able to bind apoptotic lymphoma cells equally well, M(IFN-γ/LPS) macrophages displayed enhanced ability to phagocytose them. We found that direct exposure of M(IFN-γ/LPS) macrophages to apoptotic lymphoma cells caused switching towards a protumor activation state (often referred to as M2-like) with concomitant inhibition of antitumor activity that was a characteristic feature of M(IFN-γ/LPS) macrophages. Indeed, M(IFN-γ/LPS) macrophages exposed to apoptotic lymphoma cells displayed increased lymphoma growth-promoting activities. Antilymphoma activity by M(IFN-γ/LPS) macrophages was mediated, in part, by galectin-3, a pleiotropic glycoprotein involved in apoptotic cell clearance that is strongly expressed by lymphoma TAMs but not lymphoma cells. Intriguingly, aggressive lymphoma growth was markedly impaired in mice deficient in galectin-3, suggesting either that host galectin-3-mediated antilymphoma activity is required to sustain net tumor growth or that additional functions of galectin-3 drive key oncogenic mechanisms in NHL. These findings have important implications for anticancer therapeutic approaches aimed at polarizing macrophages towards an antitumor state and identify galectin-3 as a potentially important novel target in aggressive NHL.

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Section: Discussionmentioning

confidence: 90%

Modulation of macrophage antitumor potential by apoptotic lymphoma cells

et al. 2017

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“…The concept that macrophages in the wounds of Mac‐1 −/− mice exist primarily in non‐traditional phenotypes can be explained by emerging studies on the complexity of this cell type. Recent studies have demonstrated that macrophage phenotypes might be best considered in a multi‐dimensional model . In particular, the analysis of genome‐wide transcriptional profiling of macrophages now suggests a very complex macrophage response to stress signals .…”

Section: Discussionmentioning

confidence: 99%

Wound healing in Mac‐1 deficient mice

Chen

Nagaraja

Zhou

et al. 2017

Wound Repair Regeneration

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Mac-1 (CD11b/CD18) is a macrophage receptor that plays several critical roles in macrophage recruitment and activation. Because macrophages are essential for proper wound healing, the impact of Mac-1 deficiency on wound healing is of significant interest. Prior studies have shown that Mac-1−/− mice exhibit deficits in healing, including delayed wound closure in scalp and ear wounds. The current study examined whether Mac-1 deficiency influences wound healing in small excisional and incisional skin wounds. Three millimeter diameter full thickness excisional wounds and incisional wounds were prepared on the dorsal skin of Mac-1 deficient (Mac-1 −/−) and wild type (WT) mice, and wound healing outcomes were examined. Mac-1 deficient mice exhibited a normal rate of wound closure, generally normal levels of total collagen, and nearly normal synthesis and distribution of collagens I and III. In incisional wounds, wound breaking strength was similar for Mac-1 −/− and WT mice. Wounds of Mac-1 deficient mice displayed normal total macrophage content, although macrophage phenotype markers were skewed as compared to WT. Interestingly, amounts of TGF-β1 and its downstream signaling molecules, SMAD2 and SMAD3, were significantly decreased in the wounds of Mac-1 deficient mice compared to WT. The results suggest that Mac-1 deficiency has little impact on the healing of small excisional and incisional wounds. Moreover, the findings demonstrate that the effect of single genetic deficiencies on wound healing may markedly differ among wound models. These conclusions have implications for the interpretation of the many prior studies that utilize a single model system to examine wound healing outcomes in genetically deficient mice.

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“…Because knockdown of whole genes may lead to unanticipated off-target effects, identifying disease-relevant isoform-level differences in a tissue- or cell-specific manner may open the door for more selective therapeutic targeting in re-programming macrophage phenotype, a focus of increasing interest in clinical translation. 8,67,68 Here we demonstrated that M1-HMDM activation was indeed associated with many changes on the isoform level, including more than 200 differential AS events. Although the number of AS events was far fewer than the number of differentially expressed genes in M1 activation, these AS events were enriched for a network of biologically relevant genes involved in macrophage functions such as autophagy (e.g., PLD1 ) 69 as well as immune processes (e.g., CD74 and TLR4 ), 70-73 all of which are linked to the modulation of macrophage inflammation.…”

Section: Discussionmentioning

confidence: 63%

Transcriptome-Wide Analysis Reveals Modulation of Human Macrophage Inflammatory Phenotype Through Alternative Splicing

Lin

Núñez

et al. 2016

ATVB

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Objective Human macrophages can shift phenotype across the inflammatory M1 and reparative M2 spectrum in response to environmental challenges, but the mechanisms promoting inflammatory and cardiometabolic disease-associated M1 phenotypes remain incompletely understood. Alternative splicing (AS) is emerging as an important regulator of cellular function, yet its role in macrophage activation is largely unknown. We investigated the extent to which AS occurs in M1 activation within the cardiometabolic disease context and validated a functional-genomic cell model for studying human macrophage-related AS events. Approach and Results From deep RNA-seq of resting, M1, and M2 primary human monocyte derived macrophages, we found 3860 differentially expressed genes in M1 activation and detected 233 M1-induced AS events; the majority of AS events were cell- and M1-specific with enrichment for pathways relevant to macrophage inflammation. Using genetic variant data for 10 cardiometabolic traits, we identified in M1 activation 28 trait-associated variants within the genomic loci of 21 alternatively spliced genes and 15 variants within seven differentially expressed regulatory splicing factors. Knockdown of one such splicing factor, CELF1, in primary human macrophages led to increased inflammatory response to M1 stimulation, demonstrating CELF1's potential modulation of the M1 phenotype. Finally, we demonstrated that an induced pluripotent stem cell derived macrophage system recapitulates M1-associated AS events and provides a high-fidelity macrophage AS model. Conclusions AS plays a role in defining macrophage phenotype in a cell- and stimulus-specific fashion. Alternatively spliced genes and splicing factors with trait-associated variants may reveal novel pathways and targets in cardiometabolic diseases.

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Reprogramming of macrophages — new opportunities for therapeutic targeting

Cited by 63 publications

References 68 publications

Modulation of macrophage antitumor potential by apoptotic lymphoma cells

Modulation of macrophage antitumor potential by apoptotic lymphoma cells

Wound healing in Mac‐1 deficient mice

Transcriptome-Wide Analysis Reveals Modulation of Human Macrophage Inflammatory Phenotype Through Alternative Splicing

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