scholarly journals Paraoxonase 2 Induces a Phenotypic Switch in Macrophage Polarization Favoring an M2 Anti-Inflammatory State

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Marie Koren-Gluzer ◽  
Mira Rosenblat ◽  
Tony Hayek
Keyword(s):  
Direct Effect ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Macrophage Polarization ◽  
Atherosclerotic Lesion ◽  
Peritoneal Macrophages ◽  
M2 Response ◽  
Inflammatory State ◽  
Anti Inflammatory ◽  
Atherosclerosis Development

Inflammatory processes are involved in atherosclerosis development. Macrophages play a major role in the early atherogenesis, and they are present in the atherosclerotic lesion in two phenotypes: proinflammatory (M1) or anti-inflammatory (M2). Paraoxonase 2 (PON2) is expressed in macrophages, and it was shown to protect against atherosclerosis. Thus, the aim of our study was to analyze the direct effect of PON2 on macrophage inflammatory phenotypes. Ex vivo studies were performed with murine peritoneal macrophages (MPM) harvested from control C57BL/6 and PON2-deficient (PON2KO) mice. PON2KO MPM showed an enhanced proinflammatory phenotype compared to the control, both in the basal state and following M1 activation by IFNγand lipopolysaccharide (LPS). In parallel, PON2KO MPM also showed reduced anti-inflammatory responses in the basal state and also following M2 activation by IL-4. Moreover, the PON2-null MPM demonstrated enhanced phagocytosis and reactive oxygen species (ROS) production in the basal state and following M1 activation. The direct effect of PON2 was shown by transfecting human PON2 (hPON2) into PON2KO MPM. PON2 transfection attenuated the macrophages’ response to M1 activation and enhanced M2 response. These PON2 effects were associated with attenuation of macrophages’ abilities to phagocyte and to generate ROS. We conclude that PON2 promotes an M1 to M2 switch in macrophage phenotypes.

scholarly journals Macrophage-Derived Protein S Facilitates Apoptotic Polymorphonuclear Cell Clearance by Resolution Phase Macrophages and Supports Their Reprogramming

2018 ◽  
Vol 9 ◽  
Author(s):  
Delphine Lumbroso ◽  
Soaad Soboh ◽  
Avi Maimon ◽  
Sagie Schif-Zuck ◽  
Amiram Ariel ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Ex Vivo ◽  
Protein S ◽  
Peritoneal Macrophages ◽  
Polymorphonuclear Cells ◽  
Resolvin D1 ◽  
Resolution Of Inflammation ◽  
Arginase 1 ◽  
Anti Inflammatory

The complete resolution of inflammation requires the uptake of apoptotic polymorphonuclear cells (PMN) by local macrophages (efferocytosis) and the consequent reprogramming of the engulfing phagocytes to reparative and pro-resolving phenotypes. The tyrosine kinase receptors TYRO3, AXL, and MERTK (collectively named TAM) are fundamental mediators in regulating inflammatory responses and efferocytosis. Protein S (PROS1) is a ligand for all TAM receptors that mediates various aspects of their activity. However, the involvement of PROS1 in the resolution of inflammation is incompletely understood. Here, we report the upregulation of Pros1 in macrophages during the resolution of inflammation. Selective knockout of Pros1 in the myeloid lineage significantly downregulated macrophage pro-resolving properties. Hence, Pros1-deficient macrophages engulfed fewer apoptotic PMN remnants in vivo, and exogenous PROS1 rescued impaired efferocytosis ex vivo. Moreover, Pros1-deficient peritoneal macrophages secreted higher levels of the pro-inflammatory mediators TNFα and CCL3, while they secreted lower levels of the reparative/anti-inflammatory IL-10 following exposure to lipopolysaccharide in comparison to their WT counterparts. Moreover, Pros1-deficient macrophages expressed less of the anti-inflammatory/pro-resolving enzymes arginase-1 and 12/15-lipoxygenase and produced less of the specialized pro-resolving mediator resolvin D1. Altogether, our results suggest that macrophage-derived PROS1 is an important effector molecule in regulating the efferocytosis, maturation, and reprogramming of resolution phase macrophages, and imply that PROS1 could provide a new therapeutic target for inflammatory and fibrotic disorders.

scholarly journals p38/AP-1 Pathway in Lipopolysaccharide-Induced Inflammatory Responses Is Negatively Modulated by Electrical Stimulation

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Deok Jeong ◽  
Jaehwi Lee ◽  
Young-Su Yi ◽  
Yanyan Yang ◽  
Kyoung Won Kim ◽  
...  
Keyword(s):  
Electrical Stimulation ◽  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Physiological Role ◽  
Peritoneal Macrophages ◽  
Cellular Level ◽  
Transcriptional Level ◽  
Weak Current ◽  
Anti Inflammatory

Electrical stimulation with a weak current has been demonstrated to modulate various cellular and physiological responses, including the differentiation of mesenchymal stem cells and acute or chronic physical pain. Thus, a variety of investigations regarding the physiological role of nano- or microlevel currents at the cellular level are actively proceeding in the field of alternative medicine. In this study, we focused on the anti-inflammatory activity of aluminum-copper patches (ACPs) under macrophage-mediated inflammatory conditions. ACPs generated nanolevel currents ranging from 30 to 55 nA in solution conditions. Interestingly, the nanocurrent-generating aluminum-copper patches (NGACPs) were able to suppress both lipopolysaccharide-(LPS-) and pam3CSK-induced inflammatory responses such as NO and PGE2production in both RAW264.7 cells and peritoneal macrophages at the transcriptional level. Through immunoblotting and immunoprecipitation analyses, we found that p38/AP-1 could be the major inhibitory pathway in the NGACP-mediated anti-inflammatory response. Indeed, inhibition of p38 by SB203580 showed similar inhibitory activity of the production of TNF-αand PGE2and the expression of TNF-αand COX-2 mRNA. These results suggest that ACP-induced nanocurrents alter signal transduction pathways that are involved in the inflammatory response and could therefore be utilized in the treatment of various inflammatory diseases such as arthritis and colitis.

scholarly journals The effect of coal-derived humic substances and their silver-containing bionanocomposites on arginine balance in peritoneal macrophages of intact mice

2022 ◽  
Vol 20 (4) ◽  
pp. 71-78
Author(s):  
E. S. Trofimova ◽  
M. V. Zykova ◽  
M. G. Danilets ◽  
A. A. Ligacheva ◽  
E. Yu. Sherstoboev ◽  
...  
Keyword(s):  
Humic Substances ◽  
Chronic Wounds ◽  
Macrophage Polarization ◽  
Antigen Presenting Cells ◽  
Peritoneal Macrophages ◽  
Research Area ◽  
The Body ◽  
M1 Macrophage ◽  
Anti Inflammatory ◽  
Antigen Presenting

Background. Antigen-presenting cells (APCs), especially macrophages, play an important role in the body defense against various pathogens. Their dysfunction and polarization are associated with most inflammatory and autoimmune diseases. The inflammatory process is regulated by activation and / or inhibition of genes differentially expressed by macrophages. Successful correction of inflammation leads firstly to elimination of inflammatory stimuli and then to remodeling and restoration of tissues and organs. It was experimentally confirmed that silvercontaining bionanocomposites based on natural humic substances (HS) obtained from coal of different origin, as well as initial matrices of these HS, are capable of activating pro- and anti-inflammatory properties of macrophages.Aim. To study cytotoxic, pyrogenic, and immunomodulatory properties (arginine balance) of initial HS samples and samples of silver nanoparticles ultradispersed in these HS matrices (HS-AgNPs) in the cell culture of peritoneal macrophages, as well as their effect on pro- and anti-inflammatory properties of APCs.Materials and methods. Cultural and biochemical methods were used in the study.Results. The study showed that the samples CHE-K, CHE-AgNPs, CHS-K, and CHP-K increased M1 macrophage polarization due to stimulation of the NO-synthase activity and inhibition of arginase. The samples CHI-K, CHIAgNPs, CHP-AgNPs, and CHS-AgNPs modulated an alternative M2 or M2-like state of macrophage activation. At the same time, HS are not cytotoxic at effective concentrations, and three out of four studied samples did not contain pyrogenic impurities.Conclusion. The use of HS and their silver-containing bionanocomposites, which have the ability to greatly affect the polarization of antigen-presenting cells, is a promising research area in correction of the inflammatory response for solving an important social and medical problem of treating chronic wounds. 

Abstract 553: Siglec-1 (CD169) on Monocytes/Macrophages: A New Receptor For Extracellular Self-RNA in Triggering Inflammatory Responses via the Sheddase TACE/ADAM17

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Hector A Cabrera-Fuentes ◽  
Klaus T Preissner ◽  
William A Boisvert
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Transmembrane Protein ◽  
Macrophage Polarization ◽  
Extracellular Rna ◽  
Tnf Α ◽  
M1 Phenotype ◽  
Phenotype Markers ◽  
Anti Inflammatory

As an important component of atherosclerosis, monocytes/macrophages respond to external stimuli with rapid changes in their expression of many inflammation-related genes to undergo polarization towards the M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotype. Although sialoadhesin (Sn), also known as SIGLEC-1 or CD169, is a transmembrane protein receptor expressed on monocytes and macrophages whether it has a role in macrophage polarization and ultimately, macrophage-driven atherogenesis, has not been investigated. We have previously shown that, independently of Toll-like receptor signaling, extracellular RNA (eRNA) could exert pro-thrombotic and pro-inflammatory properties in the cardiovascular system by inducing cytokine mobilization. In the current study, recombinant mouse macrophage CSF[[Unable to Display Character: –]]driven bone marrow-derived macrophage (BMDM) differentiation was found to be skewed towards the M1 phenotype by exposure of cells to eRNA. This resulted in up-regulation of inflammatory markers, whereas anti-inflammatory genes were significantly down-regulated by eRNA. Interestingly, eRNA was released from BMDM under hypoxia and induced TNF-α liberation by activating TNF-α converting enzyme (TACE) to provoke inflammation. Conversely, TNF-α promoted eRNA release, especially under hypoxia, feeding a vicious cycle of cell damage. Administration of RNase1 or TAPI (a TACE-inhibitor) prevented the production of inflammatory mediators. Murine BMDM isolated from mice deficient in sialoadhesin had the opposite reaction to eRNA treatment with a prominent down-regulation of pro-inflammatory cytokines/M1 phenotype markers, while anti-inflammatory cytokines/M2 phenotype markers were significantly raised. In keeping with the proposed role of eRNA as a pro-inflammatory “alarm signal”, these data further shed light on the role of eRNA in macrophage function in the context of chronic inflammatory diseases such as atherosclerosis. The identification of sialoadhesin as putative eRNA recognition site on macrophages may allow further investigation of the underlying mechanisms of eRNA-macrophage interaction and related signal transduction pathways. Siglec-1 thereby may provides a new target to treat eRNA-mediated vascular diseases.

scholarly journals Effect of Kramecyne on the Inflammatory Response in Lipopolysaccharide-Stimulated Peritoneal Macrophages

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
E. Sánchez-Miranda ◽  
J. Lemus-Bautista ◽  
S. Pérez ◽  
J. Pérez-Ramos
Keyword(s):  
Nitric Oxide ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Peritoneal Macrophages ◽  
Anti Inflammatory ◽  
Oxide Synthase ◽  
North And South America ◽  
North And South ◽  
Mouse Peritoneal Macrophages ◽  
Necrosis Factor

Kramecyne is a new peroxide, it was isolated fromKrameria cytisoides, methanol extract, and this plant was mostly found in North and South America. This compound showed potent anti-inflammatory activity; however, the mechanisms by which this compound exerts its anti-inflammatory effect are not well understood. In this study, we examined the effects of kramecyne on inflammatory responses in mouse lipopolysaccharide- (LPS-) induced peritoneal macrophages. Our findings indicate that kramecyne inhibits LPS-induced production of tumor necrosis factor (TNF-α) and interleukin- (IL-) 6. During the inflammatory process, levels of cyclooxygenase- (COX-) 2, nitric oxide synthase (iNOS), and nitric oxide (NO) increased in mouse peritoneal macrophages; however, kramecyne suppressed them significantly. These results provide novel insights into the anti-inflammatory actions and support its potential use in the treatment of inflammatory diseases.

Aloe Metabolites Prevent LPS-Induced Sepsis and Inflammatory Response by Inhibiting Mitogen-Activated Protein Kinase Activation

2017 ◽  
Vol 45 (04) ◽  
pp. 847-861 ◽  
Author(s):  
Chia-Yang Li ◽  
Katsuhiko Suzuki ◽  
Yung-Li Hung ◽  
Meng-Syuan Yang ◽  
Chung-Ping Yu ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Aloe Vera ◽  
Peritoneal Macrophages ◽  
Mitogen Activated Protein Kinase ◽  
Protective Effects ◽  
Raw264.7 Macrophages ◽  
Mitogen Activated Protein ◽  
Anti Inflammatory

Aloe, a polyphenolic anthranoid-containing Aloe vera leaves, is a Chinese medicine and a popular dietary supplement worldwide. In in vivo situations, polyphenolic anthranoids are extensively broken down into glucuronides and sulfate metabolites by the gut and the liver. The anti-inflammatory potential of aloe metabolites has not been examined. The aim of this study was to investigate the anti-inflammatory effects of aloe metabolites from in vitro (lipopolysaccharides (LPS)-activated RAW264.7 macrophages) and ex vivo (LPS-activated peritoneal macrophages) to in vivo (LPS-induced septic mice). The production of proinflammatory cytokines (TNF-[Formula: see text] and IL-12) and NO was determined by ELISA and Griess reagents, respectively. The expression levels of iNOS and MAPKs were analyzed by Western blot. Our results showed that aloe metabolites inhibited the expression of iNOS, decreased the production of TNF-[Formula: see text], IL-12, and NO, and suppressed the phosphorylation of MAPKs by LPS-activated RAW264.7 macrophages. In addition, aloe metabolites reduced the production of NO, TNF-[Formula: see text] and IL-12 by murine peritoneal macrophages. Furthermore, aloe administration significantly reduced the NO level and exhibited protective effects against sepsis-related death in LPS-induced septic mice. These results suggest that aloe metabolites exerted anti-inflammatory effects in vivo, and that these effects were associated with the inhibition of inflammatory mediators. Therefore, aloe could be considered an effective therapeutic agent for the treatment of sepsis.

scholarly journals Protective Role of C3aR (C3a Anaphylatoxin Receptor) Against Atherosclerosis in Atherosclerosis-Prone Mice

2020 ◽  
Vol 40 (9) ◽  
pp. 2070-2083
Author(s):  
Lin-Lin Wei ◽  
Ning Ma ◽  
Kun-Yi Wu ◽  
Jia-Xing Wang ◽  
Teng-Yue Diao ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Protective Role ◽  
Plaque Burden ◽  
Aortic Tissue ◽  
M2 Macrophage ◽  
Proinflammatory Mediators ◽  
Anti Inflammatory

Objective: Emerging evidence suggests that C3aR (C3a anaphylatoxin receptor) signaling has protective roles in various inflammatory-related diseases. However, its role in atherosclerosis has been unknown. The purpose of the study was to investigate the possible protective role of C3aR in aortic atherosclerosis and explore molecular and cellular mechanisms involved in the protection. Approach and Results: C3ar −/− /Apoe −/− mice were generated by cross-breeding of atherosclerosis-prone Apoe −/− mice and C3ar −/− mice. C3ar −/− /Apoe −/− mice and Apoe −/− mice (as a control) underwent high-fat diet for 16 weeks were assessed for (1) atherosclerotic plaque burden, (2) aortic tissue inflammation, (3) recruitment of CD11b + leukocytes into atherosclerotic lesions, and (4) systemic inflammatory responses. Compared with Apoe −/− mice, C3ar −/− /Apoe −/− mice developed more severe atherosclerosis. In addition, C3ar −/− /Apoe −/− mice have increased local production of proinflammatory mediators (eg, CCL2 [chemokine (C-C motif) ligand 2], TNF [tumor necrosis factor]-α) and infiltration of monocyte/macrophage in aortic tissue, and their lesional macrophages displayed an M1-like phenotype. Local pathological changes were associated with enhanced systemic inflammatory responses (ie, elevated plasma levels of CCL2 and TNF-α, increased circulating inflammatory cells). In vitro analyses using peritoneal macrophages showed that C3a stimulation resulted in upregulation of M2-associated signaling and molecules, but suppression of M1-associated signaling and molecules, supporting the roles of C3a/C3aR axis in mediating anti-inflammatory response and promoting M2 macrophage polarization. Conclusions: Our findings demonstrate a protective role for C3aR in the development of atherosclerosis and suggest that C3aR confers the protection through C3a/C3aR axis–mediated negative regulation of proinflammatory responses and modulation of macrophage toward the anti-inflammatory phenotype.

scholarly journals Activation of the Nrf2/HO-1 Pathway by Amomum villosum Extract Suppresses LPS-Induced Oxidative Stress In Vitro and Ex Vivo

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Dong-Woo Lim ◽  
Hee-Jin Choi ◽  
Sun-Dong Park ◽  
Hyuck Kim ◽  
Ga-Ram Yu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Ethanol Extract ◽  
Peritoneal Macrophages ◽  
Raw 264.7 Cells ◽  
Heme Oxygenase 1 ◽  
Raw 264.7 ◽  
Related Factor ◽  
Anti Inflammatory

Despite its deleterious effects on living cells, oxidative stress plays essential roles in normal physiological processes and provides signaling molecules for cell growth, differentiation, and inflammation. Macrophages are equipped with antioxidant mechanisms to cope with intracellular ROS produced during immune response, and Nrf2 (NF-E2-related factor 2)/HO-1 (heme oxygenase-1) pathway is an attractive target due to its protective effect against ROS-induced cell damage in inflamed macrophages. We investigated the effects of ethanol extract of A. villosum (AVEE) on lipopolysaccharide- (LPS-) stimulated inflammatory responses generated via the Nrf2/HO-1 signaling pathway in murine peritoneal macrophages and RAW 264.7 cells. AVEE was found to suppress the NF-κB signaling pathway, thus, to reduce proinflammatory cytokine, nitric oxide, and prostaglandin levels in peritoneal macrophages and Raw 264.7 cells treated with LPS, and to enhance HO-1 expression by activating Nrf2 signaling. Furthermore, these anti-inflammatory effects of AVEE were diminished when cells were pretreated with SnPP (a HO-1 inhibitor). HPLC analysis revealed AVEE contained quercetin, a possible activator of the Nrf2/HO-1 pathway. These results show A. villosum ethanol extract exerts anti-inflammatory effects by activating the Nrf2/HO-1 pathway in LPS-stimulated macrophages.

Novel Concentration-Dependent Roles for Heparin in Modifying LPS-Induced Activation of Mononuclear Cells in Whole Blood.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 927-927
Author(s):  
Helene Hochart ◽  
Vince Jenkins ◽  
Owen P. Smith ◽  
Barry White ◽  
James O’Donnell
Keyword(s):  
Whole Blood ◽  
Mononuclear Cells ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Anticoagulant Activity ◽  
Serum Free ◽  
Anti Inflammatory ◽  
Serum Free Conditions ◽  
Dose Dependent ◽  
Stimulation Of

Abstract Background: In addition to their etsblished anticoagulant activity, unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are known to possess clinically important immuno-modulatory properties. However different studies have reported conflicting pro- and anti-inflammatory effects in association with heparin. Moreover, the molecular basis for these heparin effects on inflammation remains unclear. In view of the wide and diverse clinical indications for heparin, it is clearly of direct translational relevance to define how UFH and LMWH differentially regulate inflammatory responses to LPS in-vivo. Objectives: To determine how UFH and LMWH regulate lipopolysaccharide (LPS)-induced activation of human mononuclear cells in whole blood, and define the role of lipopolysaccharide binding protein (LBP) in mediating this effect. Methods: Whole blood was pre-treated with UFH or LMWH (0.1–200 IU/ml), prior to stimulation with LPS (10ng/ml). After 6 hours, monocyte pro-inflammatory cytokine (interleukin (IL)-1b, IL-6, IL-8, and TNF-a) secretion was determined by plasma ELISA. Parallel experiments using THP-1 cell line and primary monocytes were performed under serum-free conditions, in the presence or absence of varying doses of recombinant human LBP (range: 50–100nM). Results: Under serum-free conditions, heparin demonstrated dose-dependent anti -inflammatory effects, significantly reducing secretion of pro-inflammatory cytokines (IL-1b, IL-6, IL-8, and TNF-a) in response to LPS-stimulation of THP-1 cells and primary monocytes. In contrast, in the presence of LBP, both UFH and LMWH demonstrated dose-dependent pro-inflammatory effects at all heparin concentrations. In ex-vivo whole blood experiments, pro-inflammatory effects (increased IL-1b and IL-8 following LPS-stimulation) of heparin were also observed, but only at supra-therapeutic doses (10–200IU/ml). Conclusion: In keeping with previous reports, we have demonstrated that both UFH and LMWH can significantly down-regulate cytokine (TNF-a, IL-1b, IL-6 and IL-8) secretion in response to LPS-activation in-vitro. However our novel data demonstrate that the effect of heparin on monocyte activation by LPS is significantly more complex in the setting of whole blood. Firstly, in contrast to the anti-inflammatory effects observed under serum-free conditions, we found that in whole blood, high concentrations of heparin exerted marked pro-inflammatory effects. Secondly we have also demonstrated that the effects of heparin in whole blood are entirely dependent upon heparin concentration and LBP concentration.

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.

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