scholarly journals Phenylbutyrate facilitates homeostasis of non-resolving inflammatory macrophages

2019 ◽  
Vol 26 (1) ◽  
pp. 62-72 ◽  
Author(s):  
Allison Rahtes ◽  
Kisha Pradhan ◽  
Mimosa Sarma ◽  
David Xie ◽  
Chang Lu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Low Dose ◽  
Inflammatory Diseases ◽  
Macrophage Polarization ◽  
Related Factor ◽  
Inflammatory Monocytes ◽  
Inflammatory Protein ◽  
Anti Inflammatory ◽  
Inflammation Resolution ◽  
Ccl2 Gene

Non-resolving inflammatory monocytes/macrophages are critically involved in the pathogenesis of chronic inflammatory diseases. However, mechanisms of macrophage polarization are not well understood, thus hindering the development of effective strategies to promote inflammation resolution. In this study, we report that macrophages polarized by subclinical super-low dose LPS preferentially expressed pro-inflammatory mediators such as ccl2 (which encodes the protein monocyte chemo attractant protein-1) with reduced expression of anti-inflammatory/homeostatic mediators such as slc40a1 (which encodes the protein ferroportin-1). We observed significantly elevated levels of the autophagy-associated and pro-inflammatory protein p62 in polarized macrophages, closely correlated with the inflammatory activation of ccl2 gene expression. In contrast, we noted a significant increase of ubiquitinated/inactive nuclear-erythroid-related factor 2 (NRF2), consistent with reduced slc40a1 gene expression in polarized macrophages. Addition of the homeostatic restorative agent phenylbutyrate (4-PBA) effectively reduced cellular levels of p62 as well as ccl2 gene induction by super-low dose LPS. On the other hand, application of 4-PBA also blocked the accumulation of ubiquitinated NRF2 and restored anti-inflammatory slc40a1 gene expression in macrophages. Together, our study provides novel insights with regard to macrophage polarization and reveals 4-PBA as a promising molecule in restoring macrophage homeostasis.

scholarly journals Nepetoidin B from Salvia plebeia R. Br. Inhibits Inflammation by Modulating the NF-κB and Nrf2/HO-1 Signaling Pathways in Macrophage Cells

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1208
Author(s):  
Mina Kim ◽  
Ji Yeong Kim ◽  
Hee Sun Yang ◽  
Jeong-Sook Choe ◽  
In Guk Hwang
Keyword(s):  
Defense Mechanisms ◽  
Inflammatory Diseases ◽  
Cell Damage ◽  
Treated Group ◽  
Raw 264.7 Cells ◽  
Resonance Spectroscopy ◽  
Raw 264.7 ◽  
Related Factor ◽  
Anti Inflammatory ◽  
Factor Α

Salvia plebeia has been used to treat a variety of inflammatory diseases, as well as colds and bronchitis. Macrophages have antioxidant defense mechanisms to cope with the intracellular reactive oxygen species (ROS) produced as part of the immune response. The nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase (HO)-1 pathway in inflamed macrophages is an appealing target due to its protective effect against ROS-induced cell damage. In this study, nepetoidin B (NeB) was first isolated from S. plebeia and identified by nuclear magnetic resonance spectroscopy. NeB reduced pro-inflammatory mediators (nitric oxide and prostaglandin E2) and cytokines (tumor necrosis factor-α, interleukin (IL)-6, and IL-1β) in LPS-activated RAW 264.7 cells by inhibiting the NF-κB signaling pathway. In the NeB-treated group, catalase and superoxide dismutase levels were significantly higher, and ROS expression decreased. By activating Nrf2 signaling, NeB enhanced HO-1 expression. Furthermore, when the cells were pretreated with tin protoporphyrin (an HO-1 inhibitor), the anti-inflammatory effects of NeB were reduced. Therefore, NeB may activate the Nrf2/ HO-1 pathway. These results reveal the NeB isolated from S. plebeia exerts anti-inflammatory effects by modulating NF-κB signaling and activating the Nrf2/HO-1 pathway in LPS-stimulated RAW 264.7 cells.

scholarly journals Tackling Chronic Inflammation with Withanolide Phytochemicals—A Withaferin A Perspective

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1107
Author(s):  
Emilie Logie ◽  
Wim Vanden Berghe
Keyword(s):  
Chronic Inflammation ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Withaferin A ◽  
Related Factor ◽  
Nuclear Factor ◽  
Pharmaceutical Drugs ◽  
In Vivo Models ◽  
Chronic Inflammatory Diseases ◽  
Anti Inflammatory

Chronic inflammatory diseases are considered to be one of the biggest threats to human health. Most prescribed pharmaceutical drugs aiming to treat these diseases are characterized by side-effects and negatively affect therapy adherence. Finding alternative treatment strategies to tackle chronic inflammation has therefore been gaining interest over the last few decades. In this context, Withaferin A (WA), a natural bioactive compound isolated from Withania somnifera, has been identified as a promising anti-cancer and anti-inflammatory compound. Although the majority of studies focus on the molecular mechanisms of WA in cancer models, recent evidence demonstrates that WA also holds promise as a new phytotherapeutic agent against chronic inflammatory diseases. By targeting crucial inflammatory pathways, including nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2 related factor 2 (Nrf2) signaling, WA suppresses the inflammatory disease state in several in vitro and preclinical in vivo models of diabetes, obesity, neurodegenerative disorders, cystic fibrosis and osteoarthritis. This review provides a concise overview of the molecular mechanisms by which WA orchestrates its anti-inflammatory effects to restore immune homeostasis.

scholarly journals The inflammation-resolution promoting molecule resolvin-D1 prevents atrial proarrhythmic remodelling in experimental right heart disease

2020 ◽  
Author(s):  
Roddy Hiram ◽  
Feng Xiong ◽  
Patrice Naud ◽  
Jiening Xiao ◽  
Martin Sirois ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Disease ◽  
M2 Macrophages ◽  
Gene Microarray ◽  
Resolvin D1 ◽  
Right Heart ◽  
M1 Macrophages ◽  
Anti Inflammatory ◽  
Inflammation Resolution ◽  
Inflammatory Signalling

Abstract Aims Inflammation plays a role in atrial fibrillation (AF), but classical anti-inflammatory molecules are ineffective. Recent evidence suggests that failure of inflammation-resolution causes persistent inflammatory signalling and that a novel drug-family called resolvins promotes inflammation-resolution. Right heart disease (RHD) is associated with AF; experimental RHD shows signs of atrial inflammatory-pathway activation. Here, we evaluated resolvin-therapy effects on atrial arrhythmogenic remodelling in experimental RHD. Methods and results Pulmonary hypertension and RHD were induced in rats with an intraperitoneal injection of 60 mg/kg monocrotaline (MCT). An intervention group received daily resolvin-D1 (RvD1), starting 1 day before MCT administration. Right atrial (RA) conduction and gene-expression were analysed respectively by optical mapping and qPCR/gene-microarray. RvD1 had no or minimal effects on MCT-induced pulmonary artery or right ventricular remodelling. Nevertheless, in vivo transoesophageal pacing induced atrial tachyarrhythmias in no CTRL rats vs. 100% MCT-only rats, and only 33% RvD1-treated MCT rats (P < 0.001 vs. MCT-only). Conduction velocity was significantly decreased by MCT, an effect prevented by RvD1. RHD caused RA dilation and fibrosis. RvD1 strongly attenuated RA fibrosis but had no effect on RA dilation. MCT increased RA expression of inflammation- and fibrosis-related gene-expression pathways on gene-microarray transcriptomic analysis, effects significantly attenuated by RvD1 (334 pathways enriched in MCT-rats vs. control; only 177 dysregulated by MCT with RvD1 treatment). MCT significantly increased RA content of type 1 (proinflammatory) CD68-positive M1 macrophages without affecting type 2 (anti-inflammatory) M2 macrophages. RvD1-treated MCT-rat RA showed significant reductions in proinflammatory M1 macrophages and increases in anti-inflammatory M2 macrophages vs. MCT-only. MCT caused statistically significant increases in protein-expression (western blot) of COL3A1, ASC, CASP1, CASP8, IL1β, TGFβ3, CXCL1, and CXCL2, and decreases in MMP2, vs. control. RvD1-treatment suppressed all these MCT-induced protein-expression changes. Conclusion The inflammation-resolution enhancing molecule RvD1 prevents AF-promoting RA remodelling, while suppressing inflammatory changes and fibrotic/electrical remodelling, in RHD. Resolvins show potential promise in combating atrial arrhythmogenic remodelling by suppressing ongoing inflammatory signalling.

scholarly journals Anti-Inflammatory Effects of Lasia spinosa Leaf Extract in Lipopolysaccharide-Induced RAW 264.7 Macrophages

2020 ◽  
Vol 21 (10) ◽  
pp. 3439 ◽  
Author(s):  
Thanh Q. C. Nguyen ◽  
Tran Duy Binh ◽  
Tuan L. A. Pham ◽  
Yen D. H. Nguyen ◽  
Dai Thi Xuan Trang ◽  
...  
Keyword(s):  
Leaf Extract ◽  
Inflammatory Diseases ◽  
Raw 264.7 Cells ◽  
Inflammatory Factors ◽  
Heme Oxygenase 1 ◽  
Raw 264.7 ◽  
Related Factor ◽  
Nuclear Factor ◽  
Raw 264.7 Macrophages ◽  
Anti Inflammatory

Lasia spinosa (L.) Thwaites was used as a traditional medicine to treat many inflammatory diseases for centuries. However, its effects on the inflammatory response are not yet characterized. In this study, we investigated the anti-inflammatory activities of L. spinosa leaf extract in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. We found that ethanol extracts of L. spinosa leaves showed anti-oxidant activity due to the presence of high levels of polyphenolic compounds. Treatment with the leaf extract significantly repressed the production of inflammatory mediators such as nitric oxide and reactive oxygen species and the expression of pro-inflammatory cytokines in the LPS-stimulated RAW 264.7 cells. Moreover, L. spinosa leaf extract treatment prevented activation of the nuclear factor-kappa B pathway by inhibiting nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) degradation. Furthermore, the mitogen-activated kinase and phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathways were suppressed upon treatment with the leaf extract. In addition to suppressing inflammatory factors, the extract also activated the nuclear factor erythroid 2-related factor 2/heme-oxygenase-1 pathway. We propose that L. spinosa leaf extract has the potential as an effective therapeutic agent for alleviating oxidative stress and excessive inflammation.

scholarly journals Liposomal delivery of azithromycin enhances its immunotherapeutic efficacy and reduces toxicity in myocardial infarction

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ahmed Al-Darraji ◽  
Renée R. Donahue ◽  
Himi Tripathi ◽  
Hsuan Peng ◽  
Bryana M. Levitan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Immune Cell ◽  
Macrophage Polarization ◽  
Significant Shift ◽  
Inflammatory Genes ◽  
Cardiac Recovery ◽  
Inflammatory Monocytes ◽  
Acute Myocardial Injury ◽  
Anti Inflammatory ◽  
Target Effects

Abstract A growing body of evidence shows that altering the inflammatory response by alternative macrophage polarization is protective against complications related to acute myocardial infarction (MI). We have previously shown that oral azithromycin (AZM), initiated prior to MI, reduces inflammation and its negative sequelae on the myocardium. Here, we investigated the immunomodulatory role of a liposomal AZM formulation (L-AZM) in a clinically relevant model to enhance its therapeutic potency and avoid off-target effects. L-AZM (40 or 10 mg/kg, IV) was administered immediately post-MI and compared to free AZM (F-AZM). L-AZM reduced cardiac toxicity and associated mortality by 50% in mice. We observed a significant shift favoring reparatory/anti-inflammatory macrophages with L-AZM formulation. L-AZM use resulted in a remarkable decrease in cardiac inflammatory neutrophils and the infiltration of inflammatory monocytes. Immune cell modulation was associated with the downregulation of pro-inflammatory genes and the upregulation of anti-inflammatory genes. The immunomodulatory effects of L-AZM were associated with a reduction in cardiac cell death and scar size as well as enhanced angiogenesis. Overall, L-AZM use enhanced cardiac recovery and survival after MI. Importantly, L-AZM was protective from F-AZM cardiac off-target effects. We demonstrate that the liposomal formulation of AZM enhances the drug’s efficacy and safety in an animal model of acute myocardial injury. This is the first study to establish the immunomodulatory properties of liposomal AZM formulations. Our findings strongly support clinical trials using L-AZM as a novel and clinically relevant therapeutic target to improve cardiac recovery and reduce heart failure post-MI in humans.

scholarly journals Regulation of Notch 1 signaling in THP-1 cells enhances M2 macrophage differentiation

2014 ◽  
Vol 307 (11) ◽  
pp. H1634-H1642 ◽  
Author(s):  
Reetu D. Singla ◽  
Jing Wang ◽  
Dinender K. Singla
Keyword(s):  
Notch Signaling ◽  
Proinflammatory Cytokine ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Macrophage Polarization ◽  
Cellular Stress ◽  
Culture Conditions ◽  
M2 Macrophage ◽  
Macrophage Differentiation ◽  
Anti Inflammatory

Macrophage polarization is emerging as an important area of research for the development of novel therapeutics to treat inflammatory diseases. Within the current study, the role of Notch1R in macrophage differentiation was investigated as well as downstream effects in THP-1 monocytes cultured in “inflammation mimicry” media. Interference of Notch signaling was achieved using either the pharmaceutical inhibitor DAPT or Notch1R small interfering RNA (siRNA), and Notch1R expression, macrophage phenotypes, and anti- and proinflammatory cytokine expression were evaluated. Data presented show that Notch1R expression on M1 macrophages as well as M1 macrophage differentiation is significantly elevated during cellular stress ( P < 0.05). However, under identical culture conditions, interference to Notch signaling via Notch1R inhibition mitigated these results as well as promoted M2 macrophage differentiation. Moreover, when subjected to cellular stress, macrophage secretion of proinflammatory cytokines was significantly heightened ( P < 0.05). Importantly, Notch1R inhibition not only diminished proinflammatory cytokine secretion but also enhanced anti-inflammatory protein release ( P < 0.05). Our data suggest that Notch1R plays a pivotal role in M1 macrophage differentiation and heightened inflammatory responses. Therefore, we conclude that inhibition of Notch1R and subsequent downstream signaling enhances monocyte to M2 polarized macrophage outcomes and promotes anti-inflammatory mediation during cellular stress.

scholarly journals Bistability in macrophage polarization and metabolic implications

2021 ◽  
Author(s):  
Carsten Geiß ◽  
Elvira Salas ◽  
Jose Guevara-Coto ◽  
Anne Régnier-Vigouroux ◽  
Rodrigo A Mora-Rodríguez
Keyword(s):  
Gene Expression ◽  
Feedback Loop ◽  
Dynamic Range ◽  
Inflammatory Diseases ◽  
Macrophage Polarization ◽  
Tca Cycle ◽  
Regulatory Motifs ◽  
Metabolic Gene Expression ◽  
Inhibitory Interactions

Macrophages are essential innate immune cells characterized by a high diversity and plasticity. In vitro, their full dynamic range of activation profiles include the classical pro-inflammatory (M1) and the alternative anti-inflammatory (M2) program. Bistability usually arises in biological systems that contain a positive-feedback loop or a mutually inhibitory, double-negative-feedback loop, which are common regulatory motifs reported for macrophage transitions from one activation state to the other one. This switch-like behavior of macrophage is observed at four different levels. First, a decision-making module in signal transduction includes mutual inhibitory interactions between M1 (STAT1 and NF-KB/p50-p65) and M2 (STAT3 and NF-KB/p50-p50) signaling pathways. Second, a switch-like behavior at the gene expression level includes complex network motifs of transcription factors and miRNAs. Third, those changes impact metabolic gene expression leading to several switches in energy production, NADPH and ROS production, TCA cycle functionality, biosynthesis and nitrogen metabolism. Fourth, metabolic changes are monitored by specialized metabolic sensors coupled to AMPK and mTOR activity to provide stability by maintaining the signals to promote either M1 or M2 activation. The targeting of robust molecular switches has the potential to treat a broad range of widespread diseases such as sepsis, cancer or chronic inflammatory diseases.

scholarly journals Kuwanon T and Sanggenon a Isolated from Morus alba Exert Anti-Inflammatory Effects by Regulating NF-κB and HO-1/Nrf2 Signaling Pathways in BV2 and RAW264.7 Cells

Molecules ◽  
2021 ◽  
Vol 26 (24) ◽  
pp. 7642
Author(s):  
Wonmin Ko ◽  
Zhiming Liu ◽  
Kwan-Woo Kim ◽  
Linsha Dong ◽  
Hwan Lee ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Morus Alba ◽  
Related Factor ◽  
Nuclear Factor ◽  
Anti Inflammatory ◽  
Factor Α ◽  
Oxide Synthase ◽  
Necrosis Factor

We previously investigated the methanolic extract of Morus alba bark and characterized 11 compounds from the extract: kuwanon G (1), kuwanon E (2), kuwanon T (3), sanggenon A (4), sanggenon M (5), sanggenol A (6), mulberofuran B (7), mulberofuran G (8), moracin M (9), moracin O (10), and norartocarpanone (11). Herein, we investigated the anti-inflammatory effects of these compounds on microglial cells (BV2) and macrophages (RAW264.7). Among them, 3 and 4 markedly inhibited the lipopolysaccharide (LPS)-induced production of nitric oxide in these cells, suggesting the anti-inflammatory properties of these two compounds. These compounds inhibited the production of prostaglandin E2, interleukin-6, and tumor necrosis factor-α, and the expression of inducible nitric oxide synthase and cyclooxygenase-2 following LPS stimulation. Pretreatment with 3 and 4 inhibited the activation of the nuclear factor kappa B signaling pathway in both cell types. The compounds also induced the expression of heme oxygenase (HO)-1 through the activation of nuclear factor erythroid 2-related factor 2. Suppressing the activity of HO-1 reversed the anti-inflammatory effects caused by pretreatment with 3 and 4, suggesting that the anti-inflammatory effects were regulated by HO-1. Taken together, 3 and 4 are potential candidates for developing therapeutic and preventive agents for inflammatory diseases.

Abstract 207: Differential Regulation of Monocyte/Macrophage Atherogenic Properties by Adiponectin: Role of Macrophage Polarization and Adiponectin Receptors

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Caroline M vanStijn ◽  
Jason Kim ◽  
Rajendra K Tangirala
Keyword(s):  
Gene Expression ◽  
Macrophage Polarization ◽  
Peritoneal Macrophages ◽  
Receptor Expression ◽  
Adiponectin Receptor ◽  
Human Monocytes ◽  
Functional Responses ◽  
Microarray Gene Expression ◽  
Inflammatory Conditions ◽  
Anti Inflammatory

Adiponectin, an adipocytokine produced by the adipose tissue, exerts metabolic, anti-inflammatory and anti-atherogenic effects to ameliorate diabetes and cardiovascular disease and is a potentially important therapeutic target. However, mechanisms of adiponectin vascular actions and the regulation of macrophage adiponectin receptor expression under inflammatory/atherogenic activation remain unclear. Our studies with human monocytes/macrophages revealed differential adiponectin receptor regulation in subjects with insulin-resistance. Here, we investigated adiponectin regulation of macrophage gene expression under pro- and anti-inflammatory conditions. We addressed the hypothesis that differential activation of macrophages into the classical (M1) or alternative (M2) program alters their adiponectin receptor (AdipoR1 and AdipoR2) expression. The microarray gene expression analyses in human monocytes exposed to TNF-α showed that adiponectin inhibited several inflammatory/atherogenic genes. Our studies revealed that adiponectin itself induces AdipoR1 and AdipoR2 expression in macrophages. We further investigated the effects of macrophage polarization (M1 or M2) on adiponectin receptor expression in bone marrow-derived and peritoneal macrophages. These studies demonstrated that M1 activation (IFN-γ and LPS) significantly reduced AdipoR1 and AdipoR2 expression. In contrast, M2 activation of (IL-4 or IL-10) maintains a significantly higher level of AdipoR1 and AdipoR2. In M2 activation, adiponectin receptor expression was more substantial in IL-10 than IL-4-polarized macrophages. These results provide important evidence that macrophage polarization profoundly alters their adiponectin receptor expression and thus functional responses to adiponectin. Thus, adiponectin-mediated macrophage functions are regulated by adiponectin receptor expression which is modulated by the macrophage polarization which controls their inflammatory and atherogenic properties.

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