Histone Deacetylase 3‐Directed PROTACs Have Anti‐inflammatory Potential by Blocking Polarization of M0‐like into M1‐like Macrophages
Chunlong ZhaoShipeng ChenDeng ChenClàudia Río‐BergéJianqiu ZhangPetra E. van der WoudenToos DaemenFrank J. Dekker
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Abstract:
Macrophage polarization plays a crucial role in inflammatory processes. The histone deacetylase 3 (HDAC3) has a deacetylase-independent function that can activate pro-inflammatory gene expression in lipopolysaccharide-stimulated M1-like macrophages and cannot be blocked by traditional small-molecule HDAC3 inhibitors. Here we employed the proteolysis targeting chimera (PROTAC) technology to target the deacetylase-independent function of HDAC3. We developed a potent and selective HDAC3-directed PROTAC, P7, which induces nearly complete HDAC3 degradation at low micromolar concentrations in both THP-1 cells and human primary macrophages. P7 increases the anti-inflammatory cytokine secretion in THP-1-derived M1-like macrophages. Importantly, P7 decreases the secretion of pro-inflammatory cytokines in M1-like macrophages derived from human primary macrophages. This can be explained by the observed inhibition of macrophage polarization from M0-like into M1-like macrophage. In conclusion, we demonstrate that the HDAC3-directed PROTAC P7 has anti-inflammatory activity and blocks macrophage polarization, demonstrating that this molecular mechanism can be targeted with small molecule therapeutics.Keywords:
HDAC3
Macrophage polarization
Macrophage polarization
Pathogenesis
M2 Macrophage
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Macrophage influences peripheral nerve regeneration. According to the classical M1/M2 paradigm, the M1 macrophage is an inhibitor of regeneration, while the M2 macrophage is a promoter. However, several studies have shown that M1 macrophages are indispensable for peripheral nerve repair and facilitate many critical processes in axonal regeneration. In this review, we summarized the information on macrophage polarization and focused on the activities of M1 macrophages in regeneration. We also provided some examples where the macrophage phenotypes were regulated to help regeneration. We argued that the coordination of both macrophage phenotypes might be effective in peripheral nerve repair, and a more comprehensive view of macrophages might contribute to macrophage-based immunomodulatory therapies.
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Efforts in experimental therapeutics of atherosclerosis are mostly focused on identifying candidate targets that can be exploited in developing new strategies to reduce plaque progression, induce its regression and/or improve stability of advanced lesions. Plaque macrophages are central players in all these processes, and consequently a significant amount of research is devoted to understanding mechanisms that regulate, for instance, macrophage apoptosis, necrosis or migration. Macrophage diversity is a key feature of the macrophage population in the plaque and can impact many aspects of lesion development. Thus, searching for molecular entities that contribute to atherorelevant functions of a specific macrophage type but not others may lead to identification of targets that can be exploited in phenotype selective modulation of the lesional macrophage. This however, remains an unmet goal. In recent years several studies have revealed critical functions of micro-RNAs (miRs) in mechanisms of macrophage polarization, and a number of miRs have emerged as being specific of distinctive macrophage subsets. Not only can these miRs represent the first step towards recognition of phenotype specific targets, but they may also pave the way to reveal novel atherorelevant pathways within macrophage subsets. This article discusses some of these recent findings, speculates on their potential relevance to atherosclerosis and elaborates on the prospective use of miRs to affect the function of plaque macrophages in a phenotype selective manner.
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To investigate the significance of the appearance of hepatic macrophages and expression of inflammatory factors in normal and macrophage-depleted livers, hepatic macrophages were depleted with liposome (Lipo)-encapsulated clodronate (CLD; 50 mg/kg, i.v.) followed by lipopolysaccharide (LPS) administration (0.1 mg/kg, i.p.) in F344 rats (CLD + LPS). Vehicle control rats (Lipo + LPS) received empty-Lipo before LPS. The low dose of LPS did not result in microscopic changes in the liver in either treatment group but did modulate M1 and M2 macrophage activity in Lipo + LPS rats without altering repopulating hepatic macrophages in CLD + LPS rats. LPS treatment in Lipo + LPS rats dramatically increased the M1 (IL-1β, IL-6, TNF-α, and MCP-1) but not M2 macrophage-related factors (IL-4 and CSF-1) compared to CLD + LPS rats. In the CLD + LPS rats, the M2 macrophage-related factors IL-4 and CSF-1 were elevated. In conclusion, low-dose LPS activated hepatic macrophages in rat livers without causing liver injury or stimulating repopulating hepatic macrophages. These data suggest that LPS may alter the liver microenvironment by modulating M1 or M2 macrophage-related inflammatory mediators and macrophage-based hepatotoxicity.
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Obesity and type 2 diabetes are now recognized as chronic pro-inflammatory diseases. In the last decade, the role of the macrophage in particular has become increasingly implicated in their pathogenesis. Abundant literature now establishes that monocytes get recruited to peripheral tissues (ie pancreas, liver and adipose tissue) to become resident macrophages and contribute to local inflammation, development of insulin resistance or even pancreatic dysfunction. Furthermore, an accumulation of evidence has established an important role for macrophage polarisation in the development of metabolic diseases. The general view in obesity is that there is an imbalance in the ratio of M1/M2 macrophages, with M1 “pro-inflammatory” macrophages being enhanced compared with M2 “anti-inflammatory” macrophages being down-regulated, leading to chronic inflammation and the propagation of metabolic dysfunction. However, there is emerging evidence revealing a more complex scenario with the spectrum of macrophage states exceeding well beyond the M1/M2 binary classification and confused further by human and animal models exhibiting different macrophage profiles. In this review we will discuss the recent findings regarding macrophage polarization in obesity and type 2 diabetes.
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Age-related macular degeneration (AMD) is one of the leading causes to blindness worldwide in elderly population.Innate immune system elements, such as macrophages and cytokines, play an important role in AMD pathology and pathogenesis.In AMD, macrophages can be functionally polarized into M1 (classically activated) and M2 (alternatively activated), as well as regulatory cells, in response to systems biology approaches.Imbalances in the M1 and M2 populations together with activation of retinal microglia are observed and potentially contribute to tissue degeneration.In this review, the phenomenon of macrophage polarization in AMD study was summarized, and the relationship between macrophage polarization and dry AMD, wet AMD, AMD related risk factors were discussed.
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Age-related macular degeneration; Macrophage polarization; M1 macrophage; M2 macrophage
Macrophage polarization
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Macrophage polarization
Proinflammatory cytokine
M2 Macrophage
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Objective: To build a cell model of LPS-induced hyper- and hypo-responsiveness in macrophage cells .Methods: Macrophage cell line RAW264.7 was pre-cultured with or without 10 ng/ml LPS for 18 h, then challenged with lipopolysaccharide(LPS), or MDP, Zymosan, PAF, FMLP, PMA for 24 h.The levels of TNF-α , IL-1, IL-6, IL-10 , NO and O-2 were measured.Results: LPS pretreatment markedly inhibited TNF-α NO and IL-6 production, but increased IL-1, IL-10 and O-2 release to LPS challenge.LPS pretreatment also altered macrophage responsiveness to the other stimuli.Conclusion: LPS can induce hyper- and hypo-responsiveness simultaneously in the macrophage cell lines.Changes in macrophage responsiveness depend on stimuli and effectors which are measured.
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