Abstract 18687: PARP9 and PARP14 are Novel Regulators of Macrophage Activation

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Hiroshi Iwata ◽  
Hideo Yoshida ◽  
Piero Ricchiuto ◽  
Takuya Hara ◽  
Iwao Yamada ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
High Resolution Mass Spectrometry ◽  
Macrophage Phenotype ◽  
Adp Ribosylation ◽  
Macrophage Activity ◽  
Arginase 1 ◽  
Anti Inflammatory ◽  
Unstable Plaques ◽  
Underlying Mechanisms

Background: Pro-inflammatory “M1” macrophages may promote atherogenesis, while “M2” macrophages may favor an anti-inflammatory milieu. Our global proteomics of M1 and M2 cells identified ADP-ribosylation enzymes PARP9 and PARP14 as novel regulators of macrophage activation. The present study has examined the underlying mechanisms and explored in vivo evidence for their role in vascular disease. Methods and Results: IFN gamma (M1) stimulation induced and IL-4 (M2) decreased PARP9 and PARP14 in mouse and human macrophages. siRNA silencing of PARP14 enhanced expression of M1 genes (e.g. TNFα, iNOS) and activation (phosphorylation) of pro-inflammatory STAT1 while suppressing M2 markers (e.g., Arginase 1) and anti-inflammatory STAT6. Conversely, PARP9 silencing suppressed M1 polarization and STAT1 activation. These results suggest that PARP14 inhibits and PARP9 promotes a pro-inflammatory macrophage phenotype. Co-immunoprecipitation indicated that PARP14 and PARP9 physically interact. ADP-ribosylation assays revealed that PARP9 impairs PARP14-induced ribosylation (Figure A). Targeted proteomics via high-resolution mass spectrometry demonstrated that PARP14 ADP-ribosylates at least two sites in STAT1α, which PARP9 suppressed. Mechanically injured arteries of Parp14-/- mice had accelerated lesion formation and macrophage accumulation. Peritoneal and plaque macrophages of PARP14-/- mice showed increased STAT1 phosphorylation, decreased STAT6 phosphorylation, enhanced M1 gene expression, and reduced M2 responses (Figure B, laser capture microdissection). More macrophages[[Unable to Display Character: &#61472;]]were immunoreactive for PARP9 in human “unstable” plaques than in “stable” plaques (64.6±16.2% vs. 30.8±12.3%, p<0.01, n=5). Conclusions: PARP14 and PARP9 reciprocally regulate the mechanisms of macrophage activation, offering the potential for new therapies for cardiovascular diseases and other conditions, in which macrophage activity impacts outcomes.

scholarly journals Pulsed Electromagnetic Field Inhibits Synovitis via Enhancing the Efferocytosis of Macrophages

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Junjie Ouyang ◽  
Bin Zhang ◽  
Liang Kuang ◽  
Peng Yang ◽  
Xiaolan Du ◽  
...  
Keyword(s):  
Medial Meniscus ◽  
Current Data ◽  
Pulsed Electromagnetic Field ◽  
Western Blot Assay ◽  
Anti Inflammatory ◽  
Pulsed Electromagnetic ◽  
Underlying Mechanisms ◽  
Pemf Treatment ◽  
Inflammatory Effect

Synovitis plays an important role in the pathogenesis of arthritis, which is closely related to the joint swell and pain of patients. The purpose of this study was to investigate the anti-inflammatory effects of pulsed electromagnetic fields (PEMF) on synovitis and its underlying mechanisms. Destabilization of the medial meniscus (DMM) model and air pouch inflammation model were established to induce synovitis in C57BL/6 mice. The mice were then treated by PEMF (pulse waveform, 1.5 mT, 75 Hz, 10% duty cycle). The synovitis scores as well as the levels of IL-1β and TNF-α suggested that PEMF reduced the severity of synovitis in vivo. Moreover, the proportion of neutrophils in the synovial-like layer was decreased, while the proportion of macrophages increased after PEMF treatment. In addition, the phagocytosis of apoptotic neutrophils by macrophages (efferocytosis) was enhanced by PEMF. Furthermore, the data from western blot assay showed that the phosphorylation of P38 was inhibited by PEMF. In conclusion, our current data show that PEMF noninvasively exhibits the anti-inflammatory effect on synovitis via upregulation of the efferocytosis in macrophages, which may be involved in the phosphorylation of P38.

scholarly journals Probiotic Conditioned Media Induces an Anti-Inflammatory Macrophage Phenotype In Vivo and In Vitro

2011 ◽  
Vol 140 (5) ◽  
pp. S-19
Author(s):  
Michelle Taylor ◽  
Vandana Gambhir ◽  
Curtis Noordhof ◽  
Oliver Jones ◽  
Shu-Mei He ◽  
...  
Keyword(s):  
Conditioned Media ◽  
Macrophage Phenotype ◽  
Anti Inflammatory ◽  
Inflammatory Macrophage

scholarly journals Knockdown of Leptin Receptor Affects Macrophage Phenotype in the Tumor Microenvironment Inhibiting Breast Cancer Growth and Progression

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2078
Author(s):  
Luca Gelsomino ◽  
Giuseppina Daniela Naimo ◽  
Rocco Malivindi ◽  
Giuseppina Augimeri ◽  
Salvatore Panza ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Leptin Receptor ◽  
Macrophage Phenotype ◽  
In Vivo Models ◽  
Monocyte Chemoattractant Protein 1 ◽  
Arginase 1 ◽  
The Impact

Aberrant leptin (Ob) signaling, a hallmark of obesity, has been recognized to influence breast cancer (BC) biology within the tumor microenvironment (TME). Here, we evaluated the impact of leptin receptor (ObR) knockdown in affecting BC phenotype and in mediating the interaction between tumor cells and macrophages, the most abundant immune cells within the TME. The stable knockdown of ObR (ObR sh) in ERα-positive and ERα-negative BC cells turned the tumor phenotype into a less aggressive one, as evidenced by in vitro and in vivo models. In xenograft tumors and in co-culture experiments between circulating monocytes and BC cells, the absence of ObR reduced the recruitment of macrophages, and also affected their cytokine mRNA expression profile. This was associated with a decreased expression and secretion of monocyte chemoattractant protein-1 in ObR sh clones. The loss of Ob/ObR signaling modulated the immunosuppressive TME, as shown by a reduced expression of programmed death ligand 1/programmed cell death protein 1/arginase 1. In addition, we observed increased phagocytic activity of macrophages compared to control Sh clones in the presence of ObR sh-derived conditioned medium. Our findings, addressing an innovative role of ObR in modulating immune TME, may open new avenues to improve BC patient health care.

scholarly journals Inhibition of atherogenesis by the COP9 signalosome subunit 5 in vivo

2017 ◽  
Vol 114 (13) ◽  
pp. E2766-E2775 ◽  
Author(s):  
Yaw Asare ◽  
Miriam Ommer ◽  
Florence. A. Azombo ◽  
Setareh Alampour-Rajabi ◽  
Marieke Sternkopf ◽  
...  
Keyword(s):  
Atherosclerotic Lesion ◽  
Cop9 Signalosome ◽  
Macrophage Phenotype ◽  
Ring E3 Ligase ◽  
Atherosclerotic Lesions ◽  
Arginase 1 ◽  
Proinflammatory Gene ◽  
A Subunit

Constitutive photomorphogenesis 9 (COP9) signalosome 5 (CSN5), an isopeptidase that removes neural precursor cell-expressed, developmentally down-regulated 8 (NEDD8) moieties from cullins (thus termed “deNEDDylase”) and a subunit of the cullin-RING E3 ligase-regulating COP9 signalosome complex, attenuates proinflammatory NF-κB signaling. We previously showed that CSN5 is up-regulated in human atherosclerotic arteries. Here, we investigated the role of CSN5 in atherogenesis in vivo by using mice with myeloid-specific Csn5 deletion. Genetic deletion of Csn5 in Apoe−/− mice markedly exacerbated atherosclerotic lesion formation. This was broadly observed in aortic root, arch, and total aorta of male mice, whereas the effect was less pronounced and site-specific in females. Mechanistically, Csn5 KO potentiated NF-κB signaling and proinflammatory cytokine expression in macrophages, whereas HIF-1α levels were reduced. Inversely, inhibition of NEDDylation by MLN4924 blocked proinflammatory gene expression and NF-κB activation while enhancing HIF-1α levels and the expression of M2 marker Arginase 1 in inflammatory-elicited macrophages. MLN4924 further attenuated the expression of chemokines and adhesion molecules in endothelial cells and reduced NF-κB activation and monocyte arrest on activated endothelium in vitro. In vivo, MLN4924 reduced LPS-induced inflammation, favored an antiinflammatory macrophage phenotype, and decreased the progression of early atherosclerotic lesions in mice. On the contrary, MLN4924 treatment increased neutrophil and monocyte counts in blood and had no net effect on the progression of more advanced lesions. Our data show that CSN5 is atheroprotective. We conclude that MLN4924 may be useful in preventing early atherogenesis, whereas selectively promoting CSN5-mediated deNEDDylation may be beneficial in all stages of atherosclerosis.

scholarly journals Network analysis reveals a distinct axis of macrophage activation in response to conflicting inflammatory cues

2019 ◽  
Author(s):  
Xiaji Liu ◽  
Jingyuan Zhang ◽  
Angela C. Zeigler ◽  
Anders R. Nelson ◽  
Merry L. Lindsey ◽  
...  
Keyword(s):  
Computational Model ◽  
Macrophage Activation ◽  
Expression Profiles ◽  
Interleukin 4 ◽  
Cytokine Signaling ◽  
Arginase 1 ◽  
M2 Polarization ◽  
Wide Range ◽  
Polarization Axis

AbstractMacrophages are subject to a wide range of cytokine and pathogen signals in vivo, which contribute to differential activation and modulation of inflammation. Understanding the response to multiple, often conflicting, cues that macrophages experience requires a network perspective. Here, we integrate data from literature curation and mRNA expression profiles to develop a large-scale computational model of the macrophage signaling network. In response to stimulation across all pairs of 9 cytokine inputs, the model predicted activation along the classic M1-M2 polarization axis but also a second axis of macrophage activation that distinguishes unstimulated macrophages from a mixed phenotype induced by conflicting cues. Along this second axis, combinations of conflicting stimuli, interleukin 4 (IL4) with lipopolysaccharide (LPS), interferon-γ (IFNγ), IFNβ, or tumor necrosis factor-α (TNFα), produced mutual inhibition of several signaling pathways, e.g. nuclear factor κB (NFκB) and signal transducer and activator of transcription 6 (STAT6), but also mutual activation of the phosphoinositide 3-kinases (PI3K) signaling module. In response to combined IFNγ and IL4, the model predicted genes whose expression was mutually inhibited, e.g. inducible nitric oxide synthase (iNOS) and arginase 1 (Arg1), or mutually enhanced, e.g. IL4 receptor-α (IL4Rα) and suppressor of cytokine signaling 1 (SOCS1), which was validated by independent experimental data. Knockdown simulations further predicted network mechanisms underlying functional crosstalk, such as mutual STAT3/STAT6-mediated enhancement of IL4Rα expression. In summary, the computational model predicts that network crosstalk mediates a broadened spectrum of macrophage activation in response to mixed pro- and anti-inflammatory cytokine cues, making it useful for modeling in vivo scenarios.Summary sentenceNetwork modeling of macrophage activation predicts responses to combinations of cytokines along both the M1-M2 polarization axis and a second axis associated with a mixed macrophage activation phenotype.

scholarly journals The inflammatory role of dysregulated IRS2 in pulmonary vascular remodeling under hypoxic conditions

2021 ◽  
Author(s):  
Mayumi Nakahara ◽  
Homare Ito ◽  
John T Skinner ◽  
Qing Lin ◽  
Rasa Tamosiuniene ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Signaling Pathway ◽  
Vascular Remodeling ◽  
Macrophage Activation ◽  
Ventricular Hypertrophy ◽  
Right Ventricular Hypertrophy ◽  
Activation Markers ◽  
Pulmonary Vascular Remodeling ◽  
Arginase 1 ◽  
Anti Inflammatory

Pulmonary hypertension (PH) is a devastating disease characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown previously that insulin receptor substrate 2 (IRS2), a molecule highly critical to insulin resistance and metabolism, has an anti-inflammatory role in Th2-skewed lung inflammation and pulmonary vascular remodeling. Here, we investigated the hypothesis that IRS2 has an immunomodulatory role in human and experimental PH. Expression analysis showed that IRS2 was significantly decreased in the pulmonary vasculature of patients with pulmonary arterial hypertension and in rat models of PH. In mice, genetic ablation of IRS2 enhanced the hypoxia-induced signaling pathway of Akt and Forkhead box O1 (FOXO1) in the lung tissue and increased pulmonary vascular muscularization, proliferation, and perivascular macrophage recruitment. Furthermore, mice with homozygous IRS2 gene deletion showed a significant gene dosage-dependent increase in pulmonary vascular remodeling and right ventricular hypertrophy in response to hypoxia. Functional studies with bone marrow-derived macrophages isolated from homozygous IRS2 gene-deleted mice showed that hypoxia exposure led to enhancement of the Akt and ERK signaling pathway followed by increases in the pro-PH macrophage activation markers vascular endothelial growth factor-A and arginase 1. Our data suggest that IRS2 contributes to anti-inflammatory effects by regulating macrophage activation and recruitment, which may limit the vascular inflammation, remodeling, and right ventricular hypertrophy that are seen in PH pathology. Restoring the IRS2 pathway may be an effective therapeutic approach for the treatment of PH and right heart failure.

Interleukin-35 promotes early endothelialization after stent implantation by regulating macrophage activation

2019 ◽  
Vol 133 (7) ◽  
pp. 869-884 ◽  
Author(s):  
Xianglan Liu ◽  
Ruoxi Zhang ◽  
Jingbo Hou ◽  
Jian Wu ◽  
Maomao Zhang ◽  
...  
Keyword(s):  
New Zealand ◽  
Cross Sections ◽  
Inflammatory Responses ◽  
Umbilical Vein ◽  
Neointimal Hyperplasia ◽  
Macrophage Phenotype ◽  
New Zealand White Rabbits ◽  
Anti Inflammatory

Abstract Background: Early strut coverage after sirolimus-eluting stent (SES) implantation is associated with the activation of inflammation, but the underlying mechanisms are not completely understood. The present study aimed to identify the relationship between the anti-inflammatory cytokine interleukin (IL) 35 (IL-35) and early strut coverage in vivo and in vitro. Methods: We utilized a retrospective study design to measure IL-35 levels in 68 stents from 68 patients with coronary artery disease and recorded serial optical coherence tomography (OCT) images (0 and 3 months) to assess stent endothelialization. The mechanism underlying the regulatory effects of IL-35 on macrophages and human umbilical vein endothelial cells (HUVECs) was also investigated. SESs were surgically implanted into the right common carotid arteries of 200 male New Zealand White rabbits receiving intravenous injections of IL-35 or a placebo. Results: At the 3-month OCT evaluation, complete endothelium coverage was correlated with IL-35 levels. IL-35 induced the activation of an anti-inflammatory M2-like macrophage phenotype by targeting the signal transducer and activators of transcription (STAT)1/4 signalling pathway, and IL-35-treated macrophages induced endothelial proliferation and alleviated endothelial dysfunction. IL-35-treated New Zealand White rabbits with implanted SESs showed lower percentages of cross-sections with an uncovered strut, elevated mean neointimal hyperplasia (NIH) thickness, and inhibited inflammatory responses. Conclusions: We investigated the effect of IL-35 expression on early stent endothelialization in vivo and in vitro and identified a crucial role for IL-35 in inducing the activation of an anti-inflammatory M2-like macrophage phenotype. The present study highlights a new therapeutic strategy for early stent endothelialization.

scholarly journals Evaluation of Anti-inflammatory, Anti-pyretic, Analgesic, and Hepatoprotective Properties of Terminalia macroptera

2020 ◽  
Vol 07 (02) ◽  
pp. e58-e67
Author(s):  
Mahamane Haïdara ◽  
Adama Dénou ◽  
Mohamed Haddad ◽  
Aïssata Camara ◽  
Korotoumou Traoré ◽  
...  
Keyword(s):  
Traditional Medicine ◽  
High Resolution Mass Spectrometry ◽  
Biological Activities ◽  
Traditional Healers ◽  
Potential Candidate ◽  
Murine Models ◽  
Leaf Extracts ◽  
Anti Inflammatory

AbstractIn Mali, improved traditional medicines [“Médicaments Traditionnels Améliorés”] are prepared from traditionally used medicinal plants. Recently, the Department of Traditional Medicine has identified Terminalia macroptera Guill. & Perr. (Combretaceae) as a potential candidate for an improved traditional medicine. T. macroptera is a West African medicinal plant used in Mali against various health disorders, with more than 30 different indications mentioned by traditional healers, including hepatitis, gonorrhea, fever, pain relief, and various infectious diseases (Helicobacter pylori-associated diseases). To date, validation of most of the biological activities of has been mainly carried out in vitro, except for antimalarial activities. In this study, the potential anti-inflammatory, antipyretic, analgesic, and hepatoprotective properties of T. macroptera were investigated in different murine models. Administration of T. macroptera ethanolic root and leaf extracts in rats significantly reduced pyrexia, pain, inflammation, and hepatic marker enzymes such as alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase in the different murine models used (p<0.05). A phytochemical screening of T. macroptera revealed the presence of tannins, flavonoids, saponins, anthracene derivatives, sterols, triterpenes, and sugars in both leaf and root extracts as the main phytochemical compounds. This was confirmed by qualitative analysis, liquid chromatography coupled with high-resolution mass spectrometry. T. macroptera extracts demonstrated interesting in vivo antipyretic, analgesic, anti-inflammatory, and hepatoprotective activities. Therefore, T. macroptera should be proposed and further evaluated as a potential improved traditional medicine for the treatment of liver-related disorders and for the relief of pain and fever.

scholarly journals Berbamine Exerts Anti-Inflammatory Effects via Inhibition of NF-κB and MAPK Signaling Pathways

2017 ◽  
Vol 41 (6) ◽  
pp. 2307-2318 ◽  
Author(s):  
Xiao-Jian Jia ◽  
Xi Li ◽  
Feng Wang ◽  
Han-Qing Liu ◽  
Da-Jun Zhang
Keyword(s):  
Signaling Pathways ◽  
Mapk Signaling ◽  
Inflammatory Factor ◽  
Anti Inflammatory ◽  
Underlying Mechanisms ◽  
Peritonitis Model ◽  
Mapk Signaling Pathways ◽  
Superoxide Release

Background/Aims: This study aimed to investigate the anti-inflammatory activity of Berbamine (BER), a bisbenzylisoquinoline alkaloid extracted from Berberis amurensis (Xiao Bo An), and the underlying mechanisms. Methods: Macrophages and neutrophils were treated with BER in vitro and stimulated with LPS and fMLP. The effects of BER on the expression of pro-inflammatory mediators in macrophages were evaluated with quantitative RT-PCR and ELISA. The effects of BER on the activation and superoxide release of neutrophils were determined with flow cytometry and WST-1 reduction test. The inhibitory effects of BER on the activation of signaling pathways related to inflammatory response in macrophages were evaluated by western blot analysis. In addition, a mouse peritonitis model was made by peritoneal injection of thioglycollate medium and anti-inflammatory effects of BER were investigated in vivo by quantitative analysis of pro-inflammatory factor production and leukocyte exudation. Results: BER significantly inhibited inflammatory factor expression by LPS-stimulated macrophages and suppressed activation and superoxide release of fMLP-stimulated neutrophils. In the mouse peritonitis model, BER significantly inhibited the activation of macrophages and exudation of neutrophils. According to analysis, BER significantly suppressed phosphorylation of NF-κB and MAPK (JNK and ERK1/2) signaling pathways in LPS-stimulated macrophages. Conclusions: Collectively, data from this study suggest that BER has anti-inflammatory potential, which is effected via inhibition of NF-κB and MAPK signaling pathways, and thus holds promise for treatment of inflammatory disease.

scholarly journals Nicotinic Amidoxime Derivate BGP-15, Topical Dosage Formulation and Anti-Inflammatory Effect

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2037
Author(s):  
Ágota Pető ◽  
Dóra Kósa ◽  
Ádám Haimhoffer ◽  
Pálma Fehér ◽  
Zoltán Ujhelyi ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
In Vitro Release ◽  
Antioxidant Effect ◽  
Penetration Enhancers ◽  
Drug Candidate ◽  
Uvb Radiation ◽  
Anti Inflammatory ◽  
Inflammatory Effect

BGP-15 is a Hungarian-developed drug candidate with numerous beneficial effects. Its potential anti-inflammatory effect is a common assumption, but it has not been investigated in topical formulations yet. The aim of our study was to formulate 10% BGP-15 creams with different penetration enhancers to ensure good drug delivery, improve bioavailability of the drug and investigate the potential anti-inflammatory effect of BGP-15 creams in vivo. Since the exact mechanism of the effect is still unknown, the antioxidant effect (tested with UVB radiation) and the ability of BGP-15 to decrease macrophage activation were evaluated. Biocompatibility investigations were carried out on HaCaT cells to make sure that the formulations and the selected excipients can be safely used. Dosage form studies were also completed with texture analysis and in vitro release with Franz diffusion chamber apparatus. Our results show that the ointments were able to reduce the extent of local inflammation in mice, but the exact mechanism of the effect remains unknown since BGP-15 did not show any antioxidant effect, nor was it able to decrease LPS-induced macrophage activation. Our results support the hypothesis that BGP-15 has a potential anti-inflammatory effect, even if it is topically applied, but the mechanism of the effect remains unclear and requires further pharmacological studies.

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