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 Elastin-Derived Peptides Promote Abdominal Aortic Aneurysm Formation by Modulating M1/M2 Macrophage Polarization

2016 ◽  
Vol 196 (11) ◽  
pp. 4536-4543 ◽  
Author(s):  
Matthew A. Dale ◽  
Wanfen Xiong ◽  
Jeffrey S. Carson ◽  
Melissa K. Suh ◽  
Andrew D. Karpisek ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Aneurysm Formation ◽  
Abdominal Aortic ◽  
M2 Macrophage Polarization

scholarly journals D‐series resolvins inhibit murine abdominal aortic aneurysm formation and increase M2 macrophage polarization

2016 ◽  
Vol 30 (12) ◽  
pp. 4192-4201 ◽  
Author(s):  
Nicolas H. Pope ◽  
Morgan Salmon ◽  
John P. Davis ◽  
Anuran Chatterjee ◽  
Gang Su ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Aneurysm Formation ◽  
Abdominal Aortic ◽  
M2 Macrophage Polarization

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 Eosinophils Protect Mice from Angiotensin-II Perfusion-Induced Abdominal Aortic Aneurysm

2020 ◽  
Author(s):  
Cong-Lin Liu ◽  
Xin Liu ◽  
Yuanyuan Zhang ◽  
Jing Liu ◽  
Chongzhe Yang ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Macrophage Polarization ◽  
Aortic Disease ◽  
Immunofluorescent Staining ◽  
Blood Eosinophil ◽  
Cationic Protein ◽  
Abdominal Aortic ◽  
M1 Macrophage

Rationale: Blood eosinophil (EOS) count and EOS cationic protein (ECP) associate with human cardiovascular diseases (CVD). Yet, whether EOS play a role in CVD remains untested. The current study detected EOS accumulation in human and murine abdominal aortic aneurysm (AAA) lesions, suggesting EOS participation in this aortic disease. Objective: To test whether and how EOS affect AAA growth. Methods and Results: Population-based randomized clinically controlled screening trials revealed higher blood EOS count in 579 male AAA patients than in 5,063 non-AAA control (0.236{plus minus}0.182 vs 0.211{plus minus}0.154, 109/L, P<0.001). Univariate (OR=1.381, P<0.001) and multivariate (OR=1.237, P=0.031) logistic regression analyses indicated that increased blood EOS count in AAA patients served as an independent risk factor of human AAA. Immunostaining and immunoblot analyses detected EOS accumulation and EOS cationic protein expression in human and murine AAA lesions. Results showed that EOS deficiency exacerbated AAA growth with increased lesion inflammatory cell contents, matrix-degrading protease activity, angiogenesis, cell proliferation and apoptosis, and smooth muscle cell (SMC) loss using angiotensin-II perfusion-induced AAA in Apoe -/- and EOS-deficient Apoe -/- ;∆dblGATA mice. EOS deficiency increased lesion chemokine expression, muted lesion expression of IL4 and EOS-associated-ribonuclease-1 (mEar1, human ECP homolog), and slanted M1 macrophage polarization. In cultured macrophages and monocytes, EOS-derived IL4 and mEar1 polarized M2 macrophages, suppressed CD11b+Ly6Chi monocytes, and increased CD11b + Ly6C lo monocytes. mEar1 treatment or adoptive transfer of EOS from WT and Il13 -/- mice, but not EOS from Il4 -/- mice, blocked AAA growth in Apoe -/- ∆dblGATA mice. Immunofluorescent staining and immunoblot analyses demonstrated a role for EOS IL4 and mEar1 in blocking NF-κB activation in macrophages, SMCs, and endothelial cells. Conclusions: EOS play a protective role in AAA by releasing IL4 and cationic proteins such as mEar1 to regulate macrophage and monocyte polarization and to block NF-κB activation in aortic inflammatory and vascular cells.

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 Activation of Invariant Natural Killer T Cells by α-Galactosylceramide Attenuates the Development of Angiotensin II-Mediated Abdominal Aortic Aneurysm in Obese ob/ob Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Akimichi Saito ◽  
Naoki Ishimori ◽  
Satoshi Tokuhara ◽  
Tsuneaki Homma ◽  
Mikito Nishikawa ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
T Lymphocytes ◽  
Aortic Aneurysm ◽  
Natural Killer ◽  
M2 Macrophage ◽  
Inkt Cells ◽  
Abdominal Aortic ◽  
Invariant Natural Killer ◽  
Natural Killer T

The infiltration and activation of macrophages as well as lymphocytes within the aorta contribute to the pathogenesis of abdominal aortic aneurysm (AAA). Invariant natural killer T (iNKT) cells are unique subset of T lymphocytes and have a crucial role in atherogenesis. However, it remains unclear whether iNKT cells also impact on the development of AAA. Ob/ob mice were administered angiotensin II (AngII, 1,000 ng/kg/min) or phosphate-buffered saline (PBS) by osmotic minipumps for 4 weeks and further divided into 2 groups; α-galactosylceramide (αGC; PBS-αGC; n = 5 and AngII-αGC; n = 12), which specifically activates iNKT cells, and PBS (PBS-PBS; n = 10, and AngII-PBS; n = 6). Maximal abdominal aortic diameter was comparable between PBS-PBS and PBS-αGC, and was significantly greater in AngII-PBS than in PBS-PBS. This increase was significantly attenuated in AngII-αGC without affecting blood pressure. αGC significantly enhanced iNKT cell infiltration compared to PBS-PBS. The ratio of F4/80-positive macrophages or CD3-positive T lymphocytes area to the lesion area was significantly higher in AngII-PBS than in PBS-PBS, and was significantly decreased in AngII-αGC. Gene expression of M2-macrophage specific markers, arginase-1 and resistin-like molecule alpha, was significantly greater in aortic tissues from AngII-αGC compared to AngII-PBS 1 week after AngII administration, and this increase was diminished at 4 weeks. Activation of iNKT cells by αGC can attenuate AngII-mediated AAA in ob/ob mice via inducing anti-inflammatory M2 polarized state. Activation of iNKT cells by the bioactive lipid αGC may be a novel therapeutic target against the development of AAA.

Sign in / Sign up

Export Citation Format

Share Document