scholarly journals Primary human monocytes differentiate into M2 macrophages and involve Notch-1 pathway

2017 ◽  
Vol 95 (3) ◽  
pp. 288-294 ◽  
Author(s):  
Dinender K. Singla ◽  
Jing Wang ◽  
Reetu Singla
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Cytokines ◽  
M2 Macrophage ◽  
Human Monocytes ◽  
M2 Macrophages ◽  
Notch 1 ◽  
Macrophage Differentiation ◽  
Arginase 1 ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

The current study investigates whether inhibiting the Notch-1 signaling pathway in primary human monocytes enhances M2 macrophage differentiation. We generated a primary human monocyte cell culture model to understand the effect of the Notch-1 signaling pathway. Monocytes were treated with Notch-1 inhibitors DAPT or siRNA. Our data show that there was a significant increase in the M1 macrophage population demonstrated by iNOS marker in the primary human monocytes treated with apoptotic-conditioned medium (ACM). Next, the levels of pro-inflammatory cytokines IL-6 and MCP-1, as well as TNF-α, increased in ACM media (p < 0.05). Furthermore, M1 macrophages and pro-inflammatory cytokines were reduced following DAPT or siRNA treatment. Comparatively, there was a significant increase in M2 macrophages, as demonstrated by an increase in CD206 and arginase-1 positive cells treated with DAPT or siRNA (p < 0.05). Furthermore, a significant increase in the associated anti-inflammatory cytokines IL-10 and IL-1RA was also observed with respect to control groups (p < 0.05). We conclude that blocking the Notch-1 pathway with DAPT or siRNA attenuates pro-inflammatory cytokines, enhances M2 macrophage differentiation, and increases anti-inflammatory cytokines in primary human monocytes. As a result, Notch-1 pathway inhibition has potential therapeutic applications of inflammatory disease.

scholarly journals BMP-7 attenuates adverse cardiac remodeling mediated through M2 macrophages in prediabetic cardiomyopathy

2014 ◽  
Vol 307 (5) ◽  
pp. H762-H772 ◽  
Author(s):  
Princess Urbina ◽  
Dinender K. Singla
Keyword(s):  
Cardiac Function ◽  
Inflammatory Cytokines ◽  
Cardiac Remodeling ◽  
Therapeutic Potential ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Citrate Buffer ◽  
Morphogenetic Protein ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

The main objective of this study was to determine whether or not monocyte infiltration occurs in the prediabetic (PD) heart and its role in PD cardiomyopathy. We hypothesized that the PD heart is significantly populated with monocytes and that bone morphogenetic protein (BMP)-7, a novel mediator of monocyte polarization, activates infiltrated monocytes into anti-inflammatory M2 macrophages, thereby inhibiting apoptosis and fibrosis and improving cardiac function. C57Bl6 mice were assigned to control, PD, or PD + BMP-7 groups. PD and PD + BMP-7 groups were administered streptozotocin (50 mg/kg), whereas control animals received sodium citrate buffer. Afterward, the PD + BMP-7 group was administered BMP-7 (200 μg/kg) for 3 days. Our data showed significantly increased infiltrated monocytes and associated pro-inflammatory cytokines, adverse cardiac remodeling, and heart dysfunction in the PD group ( P < 0.05). Interestingly, M2 macrophage differentiation and associated anti-inflammatory cytokines were enhanced and there were reduced adverse cardiac remodeling and improved cardiac function in the PD + BMP-7 group ( P < 0.05). In conclusion, our data suggest that PD cardiomyopathy is associated with increased monocyte infiltration and released proinflammatory cytokines, which contributes to adverse cardiac remodeling and cardiac dysfunction. Moreover, we report that BMP-7 possesses novel therapeutic potential in its ability to differentiate monocytes into M2 macrophages and confer cardiac protection in the PD heart.

scholarly journals Benznidazole Anti-Inflammatory Effects in Murine Cardiomyocytes and Macrophages Are Mediated by Class I PI3Kδ

2021 ◽  
Vol 12 ◽  
Author(s):  
Ágata C. Cevey ◽  
Paula D. Mascolo ◽  
Federico N. Penas ◽  
Azul V. Pieralisi ◽  
Aldana S. Sequeyra ◽  
...  
Keyword(s):  
Cell Line ◽  
Chagas Disease ◽  
Inflammatory Cytokines ◽  
Immune Cells ◽  
Macrophage Polarization ◽  
Catalytic Subunit ◽  
M2 Macrophage ◽  
Socs3 Expression ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Benznidazole (Bzl), the drug of choice in many countries for the treatment of Chagas disease, leads to parasite clearance in the early stages of infection and contributes to immunomodulation. In addition to its parasiticidal effect, Bzl inhibits the NF-κB pathway. In this regard, we have previously described that this occurs through IL-10/STAT3/SOCS3 pathway. PI3K pathway is involved in the regulation of the immune system by inhibiting NF-κB pathway through STAT3. In this work, the participation of PI3K in the immunomodulatory effects of Bzl in cardiac and immune cells, the main targets of Chagas disease, was further studied. For that, we use a murine primary cardiomyocyte culture and a monocyte/macrophage cell line (RAW 264.7), stimulated with LPS in presence of LY294002, an inhibitor of PI3K. Under these conditions, Bzl could neither increase SOCS3 expression nor inhibit the NOS2 mRNA expression and the release of NOx, both in cardiomyocytes and macrophages. Macrophages are crucial in the development of Chronic Chagas Cardiomyopathy. Thus, to deepen our understanding of how Bzl acts, the expression profile of M1-M2 macrophage markers was evaluated. Bzl inhibited the release of NOx (M1 marker) and increased the expression of Arginase I (M2 marker) and a negative correlation was found between them. Besides, LPS increased the expression of pro-inflammatory cytokines. Bzl treatment not only inhibited this effect but also increased the expression of typical M2-macrophage markers like Mannose Receptor, TGF-β, and VEGF-A. Moreover, Bzl increased the expression of PPAR-γ and PPAR-α, known as key regulators of macrophage polarization. PI3K directly regulates M1-to-M2 macrophage polarization. Since p110δ, catalytic subunit of PI3Kδ, is highly expressed in immune cells, experiments were carried out in presence of CAL-101, a specific inhibitor of this subunit. Under this condition, Bzl could neither increase SOCS3 expression nor inhibit NF-κB pathway. Moreover, Bzl not only failed to inhibit the expression of pro-inflammatory cytokines (M1 markers) but also could not increase M2 markers. Taken together these results demonstrate, for the first time, that the anti-inflammatory effect of Bzl depends on PI3K activity in a cell line of murine macrophages and in primary culture of neonatal cardiomyocytes. Furthermore, Bzl-mediated increase expression of M2-macrophage markers involves the participation of the p110δ catalytic subunit of PI3Kδ.

scholarly journals TissueGene-C promotes an anti-inflammatory micro-environment in a rat monoiodoacetate model of osteoarthritis via polarization of M2 macrophages leading to pain relief and structural improvement

2020 ◽  
Vol 28 (5) ◽  
pp. 1237-1252
Author(s):  
Hyeonyoul Lee ◽  
Heungdeok Kim ◽  
Jinwon Seo ◽  
Kyoungbaek Choi ◽  
Yunsin Lee ◽  
...  
Keyword(s):  
Pain Relief ◽  
Transforming Growth Factor ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Long Term Effects ◽  
Structural Improvement ◽  
Arginase 1 ◽  
Anti Inflammatory ◽  
Tgf Β1 ◽  
And Cartilage

Abstract Osteoarthritis (OA) is the most common form of arthritis, characterized by cartilage destruction, pain and inflammation in the joints. Existing medications can provide relief from the symptoms, but their effects on the progression of the disease are limited. TissueGene-C (TG-C) is a novel cell and gene therapy for the treatment of OA, comprising a mixture of human allogeneic chondrocytes and irradiated cells engineered to overexpress transforming growth factor-β1 (TGF-β1). This study aims to investigate the efficacy and mechanism of action of TG-C in a rat model of OA. Using the monosodium-iodoacetate (MIA) model of OA, we examined whether TG-C could improve OA symptoms and cartilage structure in rats. Our results showed that TG-C provided pain relief and cartilage structural improvement in the MIA OA model over 56 days. In parallel with these long-term effects, cytokine profiles obtained on day 4 revealed increased expression of interleukin-10 (IL-10), an anti-inflammatory cytokine, in the synovial lavage fluid. Moreover, the increased levels of TGF-β1 and IL-10 caused by TG-C induced the expression of arginase 1, a marker of M2 macrophages, and decreased the expression of CD86, a marker of M1 macrophages. These results suggest that TG-C exerts a beneficial effect on OA by inducing a M2 macrophage-dominant micro-environment. Cell therapy using TG-C may be a promising strategy for targeting the underlying pathogenic mechanisms of OA, reducing pain, improving function, and creating a pro-anabolic micro-environment. This environment supports cartilage structure regeneration and is worthy of further evaluation in future clinical trials.

Abstract 492: Resolvin D2 Inhibits Murine Abdominal Aortic Aneurysm and Increases M2 Macrophage Differentiation

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Nicolas H Pope ◽  
Morgan Salmon ◽  
Michael S Conte ◽  
Gorav Ailawadi ◽  
Gilbert R Upchurch
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Inflammatory Cytokines ◽  
Macrophage Polarization ◽  
Neointimal Hyperplasia ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Cytokine Analysis ◽  
Abdominal Aortic ◽  
Pro Inflammatory Cytokines

Objectives: Macrophages are critical to abdominal aortic aneurysm (AAA) formation; however, the role of anti-inflammatory M2 macrophages is not known. Resolvins have been shown to play a protective role in neointimal hyperplasia; however, their role in AAA has not been established. We hypothesized that treatment with Resolvin D2 (RvD2) attenuates murine AAA formation through alterations in macrophage polarization and cytokine expression. Methods: Male C57/B6 mice (n=9/group) of 8-12 weeks of age received RvD2 (100 ng/kg/treatment) or vehicle only every third day beginning three days prior to abdominal aortic perfusion with elastase. Aortas were harvested 14 days following elastase perfusion. Cytokine analysis (n=5/group) or confocal microscopy (n=4/group) was performed. Cytokine profiles were analyzed using a murine antibody array. To determine the effect of RvD2 on macrophage polarization, confocal staining for macrophages (Mac2), M1 (MCP-1) and M2 (Arg-1) macrophage subtypes, α-actin and 4',6-diamidino-2-phenylindole (DAPI) was utilized. Results: Mean aortic dilation was 96.23 % (± 13.07 %) for vehicle treated and 56.58% (± 9.69%) for RvD2 treated mice (p<0.0001). Pro-inflammatory cytokines CXCL-10, IL-1β, TIMP-1 and MCP-1 were significantly elevated in control as compared to RvD2 treated animals. Confocal histology demonstrated a prevalence of M2 macrophages within the aortic media in mice treated with RvD2 (Figure 1). Conclusions: Resolvin D2 exhibits a potent protective effect against experimental AAA formation. Treatment with RvD2 significantly influences macrophage polarization and decreases several important pro-inflammatory cytokines. Resolvins and the alteration of macrophage polarization represent potential future targets for prevention of AAA.

scholarly journals Decursinol Angelate Inhibits LPS-Induced Macrophage Polarization through Modulation of the NFκB and MAPK Signaling Pathways

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 1880 ◽  
Author(s):  
Salman Islam ◽  
Jung Lee ◽  
Adeeb Shehzad ◽  
Eun-Mi Ahn ◽  
You Lee ◽  
...  
Keyword(s):  
Map Kinase ◽  
Signaling Pathways ◽  
Inflammatory Cytokines ◽  
Macrophage Polarization ◽  
Raw 264.7 Cells ◽  
M2 Macrophage ◽  
Raw 264.7 ◽  
Decursinol Angelate ◽  
Anti Inflammatory ◽  
Pro Inflammatory Cytokines

Inflammation is considered the root cause of various inflammatory diseases, including cancers. Decursinol angelate (DA), a pyranocoumarin compound obtained from the roots of Angelica gigas, has been reported to exhibit potent anti-inflammatory effects. In this study, the anti-inflammatory effects of DA on the MAP kinase and NFκB signaling pathways and the expression of pro-inflammatory cytokines were investigated in phorbol 12-myristate 13-acetate (PMA)-activated human promyelocytic leukemia (HL-60) and lipopolysaccharide (LPS)-stimulated macrophage (Raw 264.7) cell lines. PMA induced the activation of the MAP kinase-NFκB pathway and the production of pro-inflammatory cytokines in differentiated monocytes. Treatment with DA inhibited the activation of MAP kinases and the translocation of NFκB, and decreased the expression and exogenous secretion of IL-1β and IL-6. Furthermore, LPS-stimulated Raw 264.7 cells were found to have increased expression of M1 macrophage-associated markers, such as NADPH oxidase (NOX) and inducible nitric oxide synthase (iNOS), and the M2 macrophage-associated marker CD11b. LPS also activated pro-inflammatory cytokines and Erk-NFκB. Treatment with DA suppressed LPS-induced macrophage polarization and the inflammatory response by blocking Raf-ERK and the translocation of NFκB in Raw 264.7 cells. Treatment with DA also inhibited the expression of pro-inflammatory cytokines, such as IL-1β and IL-6, NOX, and iNOS in Raw 264.7 cells. These results suggest that DA has the potential to inhibit macrophage polarization and inflammation by blocking the activation of pro-inflammatory signals. These anti-inflammatory effects of DA may contribute to its potential use as a therapeutic strategy against various inflammation-induced cancers.

scholarly journals Recombinant Trichinella spiralis 53-kDa protein activates M2 macrophages and attenuates the LPS-induced damage of endotoxemia

2016 ◽  
Vol 22 (6) ◽  
pp. 419-432 ◽  
Author(s):  
Zhi-bin Chen ◽  
Hao Tang ◽  
Yan-bing Liang ◽  
Wen Yang ◽  
Jing-guo Wu ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Trichinella Spiralis ◽  
Organ Damage ◽  
Secretory Protein ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Microbial Infection ◽  
M1 Macrophage ◽  
Lethal Sepsis ◽  
Anti Inflammatory

Sepsis is a serious clinical condition of excessive systemic immune response to microbial infection. The pro-inflammatory stage of sepsis is generally launched by innate cells such as macrophages. They release inflammatory cytokines, activate other immune cells and cause severe tissue/organ damage. In this study, we have revealed that recombinant Trichinella spiralis (TS) excretory–secretory protein (rTsP53) exhibited anti-inflammatory properties and rescued mice from LPS-induced endotoxemia, which is a common model for sepsis study, potentially through the induction of M2 macrophages. rTsP53 treatment significantly decreased inflammatory cytokines (IL-6, IFN-γ and TNF-α) and increased IL-4, IL-10, IL-13 and TGF-β secretion, both in circulation and in tissues. rTsP53 also induced the activation and infiltration of F4/80+CD163+ macrophages to inflammatory tissues, increased M2 macrophage-related Arg1 and Fizz1 expression, and decreased M1 macrophage-related iNOS expression. PCR array showed that rTsP53 activated several genes that involve the survival of macrophages and also anti-inflammatory genes such as SOCS3. Together, our results show that rTsP53 activates M2 macrophages, which has strong anti-inflammatory potential to prevent LPS-induced lethal sepsis.

scholarly journals Decrease of IL-1β and TNF in the Spinal Cord Mediates Analgesia Produced by Ankle Joint Mobilization in Complete Freund Adjuvant-Induced Inflammation Mice Model

2022 ◽  
Vol 12 ◽  
Author(s):  
Carlos Minoru Omura ◽  
Daniela Dero Lüdtke ◽  
Verônica Vargas Horewicz ◽  
Paula Franson Fernandes ◽  
Taynah de Oliveira Galassi ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Ankle Joint ◽  
Inflammatory Cytokines ◽  
Mechanical Hyperalgesia ◽  
M2 Macrophages ◽  
Macrophage Phenotype ◽  
Mice Model ◽  
Joint Mobilization ◽  
Arginase 1 ◽  
Pro Inflammatory Cytokines

ObjectiveThis study aims to investigate the effects of ankle joint mobilization (AJM) on mechanical hyperalgesia and peripheral and central inflammatory biomarkers after intraplantar (i.pl.) Complete Freund’s Adjuvant (CFA)-induced inflammation.MethodsMale Swiss mice were randomly assigned to 3 groups (n = 7): Saline/Sham, CFA/Sham, and CFA/AJM. Five AJM sessions were carried out at 6, 24, 48, 72, and 96 h after CFA injection. von Frey test was used to assess mechanical hyperalgesia. Tissues from paw skin, paw muscle and spinal cord were collected to measure pro-inflammatory (TNF, IL-1β) and anti-inflammatory cytokines (IL-4, IL-10, and TGF-β1) by ELISA. The macrophage phenotype at the inflammation site was evaluated by Western blotting assay using the Nitric Oxide Synthase 2 (NOS 2) and Arginase-1 immunocontent to identify M1 and M2 macrophages, respectively.ResultsOur results confirm a consistent analgesic effect of AJM following the second treatment session. AJM did not change cytokines levels at the inflammatory site, although it promoted a reduction in M2 macrophages. Also, there was a reduction in the levels of pro-inflammatory cytokines IL-1β and TNF in the spinal cord.ConclusionTaken together, the results confirm the anti-hyperalgesic effect of AJM and suggest a central neuroimmunomodulatory effect in a model of persistent inflammation targeting the pro-inflammatory cytokines IL-1β and TNF.

scholarly journals Anemoside B4 protects against Klebsiella pneumoniae- and influenza virus FM1-induced pneumonia via the TLR4/Myd88 signaling pathway in mice

2020 ◽  
Author(s):  
Jia He ◽  
Renyikun Yuan ◽  
Xiaolan Cui ◽  
Yushun Cui ◽  
Shan Han ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Molecular Docking ◽  
Signaling Pathway ◽  
Therapeutic Effect ◽  
Inflammatory Cytokines ◽  
Inflammatory Activity ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Myd88 Signaling ◽  
Pro Inflammatory Cytokines

Abstract Background: Pneumonia refers to the inflammation of the terminal airway, alveoli and pulmonary interstitium, which can be caused by pathogenic microorganisms, physical and chemical factors, immune damage, and drugs. Anemoside B4, the major ingredient of Pulsatilla chinensis (Bunge) Regel, exhibited anti-inflammatory activity. However, the therapeutic effect of anemoside B4 on pneumonia has not been unraveled. This study aims to investigate that anemoside B4 attenuates the inflammatory responses in Klebsiella pneumonia (KP)- and influenza virus FM1 (FM1)-induced pneumonia mice model.Methods: The network pharmacology and molecular docking assays were employed to predict the targets of anemoside B4’s treatment of pneumonia. Two models (bacterial KP-infected mice and virus FM1-infected mice) were employed in our study. BALB/c mice were divided into six groups: control, model group (KP- induced pneumonia or FM1-induced pneumonia), anemoside B4 (B4)-treated group (2.5, 5, 10 mg/kg), and positive drug group (Ribavirin or Ceftriaxone Sodium Injection). Blood samples were collected for hematology analysis. The effects of B4 on inflammation-associated mediators were investigated by Enzyme-linked immunosorbent assay (ELISA) and hematoxylin and eosin staining (HE) staining. Proteins expression was quantified by western blotting.Results: The network results indicated that many pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) participated in anemoside B4’s anti-inflammatory activity. The counts of neutrophil (NEU) and white blood cell (WBC), the level of myeloperoxidase (MPO), and the release of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 increased by KP or FM1 infection, which were reversed by anemoside B4. In addition, anemoside B4 significantly suppressed the FM1-induced expression of Toll-like receptor 4 (TLR4), myeloid differential protein-88 (MyD88), and myeloid differentiation protein-2 (MD-2), which were further validated by molecular docking data that anemoside B4 bound to bioactive sites of TLR4. Therefore, anemoside B4 exhibited a significant therapeutic effect on pneumonia via the TLR4/MyD88 pathway.Conclusion: Our findings demonstrated that anemoside B4 attenuates pneumonia via the TLR4/Myd88 signaling pathway, suggesting that anemoside B4 is a promising therapeutic candidate for bacterial-infected or viral-infected pneumonia.

scholarly journals Anemoside B4 protects against Klebsiella pneumoniae- and influenza virus FM1-induced pneumonia via the TLR4/Myd88 signaling pathway in mice

2020 ◽  
Author(s):  
Jia He ◽  
Renyikun Yuan ◽  
Xiaolan Cui ◽  
Yushun Cui ◽  
Shan Han ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Molecular Docking ◽  
Signaling Pathway ◽  
Therapeutic Effect ◽  
Inflammatory Cytokines ◽  
Inflammatory Activity ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Myd88 Signaling ◽  
Pro Inflammatory Cytokines

Abstract Background Pneumonia refers to the inflammation of the terminal airway, alveoli and pulmonary interstitium, which can be caused by pathogenic microorganisms, physical and chemical factors, immune damage, and drugs. Anemoside B4, the major ingredient of Pulsatilla chinensis (Bunge) Regel, exhibited anti-inflammatory activity. However, the therapeutic effect of anemoside B4 on pneumonia has not been unraveled. This study aims to investigate that anemoside B4 attenuates the inflammatory responses in Klebsiella pneumonia (KP)- and influenza virus FM1 (FM1)-induced pneumonia mice model.Methods The network pharmacology and molecular docking assays were employed to predict the targets of anemoside B4’s treatment of pneumonia. Two models (bacterial KP-infected mice and virus FM1-infected mice) were employed in our study. BALB/c mice were divided into six groups: control, model group (KP- induced pneumonia or FM1-induced pneumonia), anemoside B4 (B4)-treated group (2.5, 5, 10 mg/kg), and positive drug group (Ribavirin or Ceftriaxone Sodium Injection). Blood samples were collected for hematology analysis. The effects of B4 on inflammation-associated mediators were investigated by Enzyme-linked immunosorbent assay (ELISA). Proteins expression was quantified by western blotting.Results The network results indicated that many pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) participated in anemoside B4’s anti-inflammatory activity. The counts of neutrophil (NEU) and white blood cell (WBC), the level of myeloperoxidase (MPO), and the release of pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 increased by KP or FM1 infection, which were reversed by anemoside B4. In addition, anemoside B4 significantly suppressed the FM1-induced expression of Toll-like receptor 4 (TLR4), myeloid differential protein-88 (MyD88), and myeloid differentiation protein-2 (MD-2), which were further validated by molecular docking data that anemoside B4 bound to bioactive sites of TLR4. Therefore, anemoside B4 exhibited a significant therapeutic effect on pneumonia via the TLR4/MyD88 pathway.Conclusion Our findings demonstrated that anemoside B4 attenuates pneumonia via the TLR4/Myd88 signaling pathway, suggesting that anemoside B4 is a promising therapeutic candidate for bacterial-infected or viral-infected pneumonia.

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