Epigenetic control of macrophage polarization: implications for targeting tumor-associated macrophages

Groot, Amber E. de; Pienta, Kenneth J.

doi:10.18632/oncotarget.24556

Cited by 88 publications

(78 citation statements)

References 134 publications

(139 reference statements)

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“…3a-d), thus shifting the fraction of pro-inflammatory F4/80 + iNOS + downward and favoring an M2 phenotype. Our findings are in line with previous reports, whereby epigenetic regulation by HDIs could modulate numbers of mature MNC as well as their phenotype [27][28][29]. The novelty of this report is that MNC could be driven to transform to pro-or anti-inflammatory phenotypes, depending on the timing of HDI administration.…”

Section: Discussionsupporting

confidence: 92%

Time-dependent effects of histone deacetylase inhibition in sepsis-associated acute kidney injury

Wen

Frank

et al. 2020

ICMx

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Background: Sepsis, a dysregulated host response to infection with results in organ dysfunction, has been a major challenge to the development of effective therapeutics. Sepsis-associated acute kidney injury (S-AKI) results in a 3-5-fold increase in the risk of hospital mortality compared to sepsis alone. The development of therapies to reverse S-AKI could therefore significantly affect sepsis outcomes. However, the translation of therapies from preclinical studies into humans requires model systems that recapitulate clinical scenarios and the development of renal fibrosis indicative of the transition from acute to chronic kidney disease. Results: Here we characterized a murine model of S-AKI induced by abdominal sepsis developing into a chronic phenotype. We applied a small molecule histone deacetylase-8 inhibitor, UPHD186, and found that early treatment, beginning at 48 h post-sepsis, worsened renal outcome accompanied by decreasing mononuclear cell infiltration in the kidney, skewing cells into a pro-inflammatory phenotype, and increased pro-fibrotic gene expression, while delayed treatment, beginning at 96 h post-sepsis, after the acute inflammation in the kidney had subsided, resulted in improved survival and kidney histology presumably through promoting proliferation and inhibiting fibrosis. Conclusions: These findings not only present a clinically relevant S-AKI model, but also introduce a timing dimension into S-AKI therapeutic interventions that delayed treatment with UPHD186 may enhance renal histologic repair. Our results provide novel insights into successful repair of kidney injury and sepsis therapy.

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Section: Discussionsupporting

confidence: 92%

Time-dependent effects of histone deacetylase inhibition in sepsis-associated acute kidney injury

Wen

Frank

et al. 2020

ICMx

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“…Recent studies have highlighted that macrophages are not exempt from these epigenetic modifications because they directly affect the polarization state of macrophages. (125)(126)(127)(128)(129) Aside from macrophagedepleting agents used in mice, such as clodronate-loaded liposomes or KC depletion by gadolinium chloride, several approaches have been proposed to influence the macrophage phenotype. Macrophage-targeting delivery methods for immunomodulatory drugs or silencing RNAs (siRNAs) include the use of nanoparticles, liposomes, glucan shell microparticles, and oligopeptide complexes.…”

Section: Spectra and Fluidity Of Macrophage Polarization Statesmentioning

confidence: 99%

Liver Macrophages: Old Dogmas and New Insights

2019

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Inflammation is a hallmark of virtually all liver diseases, such as liver cancer, fibrosis, nonalcoholic steatohepatitis, alcoholic liver disease, and cholangiopathies. Liver macrophages have been thoroughly studied in human disease and mouse models, unravelling that the hepatic mononuclear phagocyte system is more versatile and complex than previously believed. Liver macrophages mainly consist of liver-resident phagocytes, or Kupffer cells (KCs), and bone marrow-derived recruited monocytes. Although both cell populations in the liver demonstrate principal functions of macrophages, such as phagocytosis, danger signal recognition, cytokine release, antigen processing, and the ability to orchestrate immune responses, KCs and recruited monocytes retain characteristic ontogeny markers and remain remarkably distinct on several functional aspects. While KCs dominate the hepatic macrophage pool in homeostasis ("sentinel function"), monocyte-derived macrophages prevail in acute or chronic injury ("emergency response team"), making them an interesting target for novel therapeutic approaches in liver disease. In addition, recent data acquired by unbiased large-scale techniques, such as single-cell RNA sequencing, unraveled a previously unrecognized complexity of human and murine macrophage polarization abilities, far beyond the old dogma of inflammatory (M1) and anti-inflammatory (M2) macrophages. Despite tremendous progress, numerous challenges remain in deciphering the full spectrum of macrophage activation and its implication in either promoting liver disease progression or repairing injured liver tissue. Being aware of such heterogeneity in cell origin and function is of crucial importance when studying liver diseases, developing novel therapeutic interventions, defining macrophage-based prognostic biomarkers, or designing clinical trials. Growing knowledge in gene expression modulation and emerging technologies in drug delivery may soon allow shaping macrophage populations toward orchestrating beneficial rather than detrimental inflammatory responses. (Hepatology Communications 2019;3:730-743). T he liver is the largest solid organ and exerts vital metabolic functions. Liver diseases leading to liver cirrhosis or cancer are increasingly challenging for public health, the current trend being an augmentation of such diseases mainly caused by changes in alimentation and life habits. (1) Liver diseases are various by nature in terms of etiologies, chronicity, and chances of recovery. However, one constant feature is the presence of liver inflammation, and most remarkably, there is an apparent compulsory association of inflammation with a poor outcome for patients. (2-6) Liver macrophages are included in the mononuclear phagocyte system and are renown cornerstones in most if not all inflammation-related liver disorders due to their ability to respond to a seemingly infinite

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“…It is also found that the normal cells show epigenetic changes once placed in the supernatant of tumour tissues, although it is not possible to determine who initiates this change. The interaction between the two is factual 21 . To illustrate this interaction, we used a simulated TME to verify the expression of ALKBH5 in ovarian cancer tissue and the related regulatory mechanism.…”

Section: Introductionmentioning

confidence: 99%

RNA demethylase ALKBH5 promotes ovarian carcinogenesis in a simulated tumour microenvironment through stimulating NF‐κB pathway

Jiang

Wan

Gong

et al. 2020

J Cellular Molecular Medi

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Methylation is the main form of RNA modification. N6‐methyladenine (m6A) regulates the splicing and translation of mRNA. Alk B homologue 5 (ALKBH5) participates in the biological regulation of various cancers. However, its role in ovarian carcinogenesis has not been unveiled. In the present study, ALKBH5 showed higher expression in ovarian cancer tissue than in normal ovarian tissue, but lower expression in ovarian cancer cell lines than in normal ovarian cell lines. Interestingly, Toll‐like receptor (TLR4), a molecular functioning in tumour microenvironment (TME), demonstrated the same expression trend. To investigate the effect of abnormal TME on ovarian carcinogenesis, we established an in vitro model in which macrophages and ovarian cancer cells were co‐cultured. In the ovarian cancer cells co‐cultured with M2 macrophages, the expression of ALKBH5 and TLR4 increased. We also verified that TLR4 up‐regulated ALKBH5 expression via activating NF‐κB pathway. Depending on transcriptome sequencing, m6A‐Seq and m6A MeRIP, we found that NANOG served as a target in ALKBH5‐mediated m6A modification. NANOG expression increased after mRNA demethylation, consequently enhancing the aggressiveness of ovarian cancer cells. In conclusion, highly expressed TLR4 activated NF‐κB pathway, up‐regulated ALKBH5 expression and increased m6A level and NANOG expression, all contributing to ovarian carcinogenesis. Our study revealed the role of m6A in ovarian carcinogenesis, providing a clue for inventing new target therapy.

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Epigenetic control of macrophage polarization: implications for targeting tumor-associated macrophages

Cited by 88 publications

References 134 publications

Time-dependent effects of histone deacetylase inhibition in sepsis-associated acute kidney injury

Time-dependent effects of histone deacetylase inhibition in sepsis-associated acute kidney injury

Liver Macrophages: Old Dogmas and New Insights

RNA demethylase ALKBH5 promotes ovarian carcinogenesis in a simulated tumour microenvironment through stimulating NF‐κB pathway

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