scholarly journals Montelukast, a Cysteinyl Leukotriene Receptor 1 Antagonist, Induces M2 Macrophage Polarization and Inhibits Murine Aortic Aneurysm Formation

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Yohei Kawai ◽  
Yuji Narita ◽  
Aika Yamawaki-Ogata ◽  
Akihiko Usui ◽  
Kimihiro Komori
Keyword(s):  
Aortic Aneurysm ◽  
Macrophage Polarization ◽  
Enzyme Linked Immunosorbent Assay ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Gene Expressions ◽  
Arginase 1 ◽  
M2 Macrophage Polarization

Background. The pathogenesis of abdominal aortic aneurysm (AAA) is characterized by atherosclerosis with chronic inflammation in the aortic wall. Montelukast is a selective cys-LT 1 receptor antagonist that can suppress atherosclerotic diseases. We evaluated the in vitro properties of montelukast and its in vivo activities in an angiotensin II–infused apolipoprotein E–deficient (apoE−/−) AAA mouse model. Methods. The mouse monocyte/macrophage cell line J774A.1 was used in vitro. M1 macrophages were treated with montelukast, and gene expressions of inflammatory cytokines were measured. Macrophages were cultured with montelukast, then gene expressions of arginase-1 and IL (interleukin)-10 were assessed by quantitative polymerase chain reaction, arginase-1 was measured by fluorescence-activated cell sorting, and IL-10 concentration was analyzed by enzyme-linked immunosorbent assay. In vivo, one group (Mont, n=7) received oral montelukast (10 mg/kg/day) for 28 days, and the other group (Saline, n=7) was given normal Saline as a control for the same period. Aortic diameters, activities of matrix metalloproteinases (MMPs), cytokine concentrations, and the number of M2 macrophages were analyzed. Results. Relative to control, montelukast significantly suppressed gene expressions of MMP-2, MMP-9, and IL-1β, induced gene expressions of arginase-1 and IL-10, enhanced the expression of the arginase-1 cell surface protein, and increased the protein concentration of IL-10. In vivo, montelukast significantly decreased aortic expansion (Saline vs Mont; 2.44 ± 0.15 mm vs 1.59 ± 0.20 mm, P<.01), reduced MMP-2 activity (Saline vs Mont; 1240 μM vs 755 μM, P<.05), and induced infiltration of M2 macrophages (Saline vs Mont; 7.51 % vs 14.7 %, P<.05). Conclusion. Montelukast induces M2 macrophage polarization and prevents AAA formation in apoE−/− mice.

scholarly journals Hexapeptide induces M2 macrophage polarization via the JAK1/STAT6 pathway to promote angiogenesis in bone repair

2021 ◽  
Author(s):  
Xinyun Han ◽  
Junxian Hu ◽  
Wenbo Zhao ◽  
Hongwei Lu ◽  
Jingjin Dai ◽  
...  
Keyword(s):  
Bone Repair ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Promising Alternative ◽  
Defect Repair ◽  
M2 Macrophage Polarization ◽  
Underlying Mechanisms ◽  
Main Regulator

Abstract Angiogenesis is essential for successful bone defect repair. In normal tissue repair, the physiological inflammatory response is the main regulator of angiogenesis through the activity of macrophages and the cytokines secreted by them. In particular, M2 macrophages which secrete high levels of PDGF-BB are typically considered to promote angiogenesis. A hexapeptide [WKYMVm, (Trp-Lys-Tyr-Met-Val-D-Met-NH2)] has been reported to modulate inflammatory activities. However, the underlying mechanisms by which WKYMVm regulates macrophages remain unclear. In this study, the possible involvement by which WKYMVm induces the polarization of macrophages and affects their behaviors was evaluated. In vitro results showed that macrophages were induced to an M2 rather than M1 phenotype and the M2 phenotype was enhanced by WKYMVm through activation of the JAK1/STAT6 signaling pathway. It was also found that WKYMVm played an important role in the PDGF-BB production increase and proangiogenic abilities in M2 macrophages. Consistent with the results in vitro, the elevated M2/M0 ratio induced by WKYMVm enhanced the formation of new blood vessels in a femoral defect mouse model. In summary, these findings suggest that WKYMVm could be a promising alternative strategy for angiogenesis in bone repair by inducing M2 macrophage polarization.

scholarly journals A novel delivery nanobiotechnology: engineered miR-181b exosomes improved osteointegration by regulating macrophage polarization

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Wei Liu ◽  
Muyu Yu ◽  
Feng Chen ◽  
Longqing Wang ◽  
Cheng Ye ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Macrophage Polarization ◽  
Underlying Mechanism ◽  
M2 Macrophage ◽  
Implant Loosening ◽  
M2 Polarization ◽  
M2 Macrophage Polarization ◽  
Osteogenesis In Vitro

Abstract Background Many patients suffer from implant loosening after the implantation of titanium alloy caused by immune response to the foreign bodies and this could inhibit the following osteogenesis, which could possibly give rise to aseptic loosening and poor osteointegration while there is currently no appropriate solution in clinical practice. Exosome (Exo) carrying miRNA has been proven to be a suitable nanocarrier for solving this problem. In this study, we explored whether exosomes overexpressing miR-181b (Exo-181b) could exert beneficial effect on promoting M2 macrophage polarization, thus inhibiting inflammation as well as promoting osteogenesis and elaborated the underlying mechanism in vitro. Furthermore, we aimed to find whether Exo-181b could enhance osteointegration. Results In vitro, we firstly verified that Exo-181b significantly enhanced M2 polarization and inhibited inflammation by suppressing PRKCD and activating p-AKT. Then, in vivo, we verified that Exo-181b enhanced M2 polarization, reduced the inflammatory response and enhanced osteointegration. Also, we verified that the enhanced M2 polarization could indirectly promote the migration and osteogenic differentiation by secreting VEGF and BMP-2 in vitro. Conclusions Exo-181b could suppress inflammatory response by promoting M2 polarization via activating PRKCD/AKT signaling pathway, which further promoting osteogenesis in vitro and promote osteointegration in vivo. Graphic abstract

scholarly journals Pirfenidone Modulates Macrophage Polarization and Ameliorates Radiation-induced Lung Fibrosis by Inhibiting the TGF-β1/Smad3 Pathway

2020 ◽  
Author(s):  
hangjie ying ◽  
min Fang ◽  
Qing Qing Hang ◽  
Ya mei Chen ◽  
Xu Qian ◽  
...  
Keyword(s):  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Macrophage Polarization ◽  
Macrophage Infiltration ◽  
M2 Macrophage ◽  
Arginase 1 ◽  
Radiation Induced ◽  
M2 Macrophage Polarization ◽  
Tgf Β1

Abstract Background：Radiation-induced lung injury (RILI) mainly contributes to the complications of thoracic radiotherapy. RILI can be divided into early-stage radiation pneumonia (RP) and late-stage radiation-induced lung fibrosis (RILF). Once RILF occurs, patients will eventually develop irreversible respiratory failure; thus, a new treatment strategy to prevent RILI is urgently needed. This study explored the therapeutic effect of pirfenidone (PFD), a Food and Drug Administration (FDA)-approved drug for idiopathic pulmonary fibrosis (IPF) treatment, and its mechanism in the treatment of RILF. Methods：A series of in vitro and in vivo assays were performed to explore the role and mechanism of PFD in the prevention and treatment of RILF. Results：Collagen deposition and fibrosis in the lung were reversed by PFD treatment, which was associated with reduced M2 macrophage infiltration and inhibition of the transforming growth factor-β1(TGF-β1) /drosophila mothers against decapentaplegic 3 (Smad3) signaling pathway. Moreover, PFD treatment decreased the radiation-induced expression of TGF-β1 and phosphorylation of Smad3 in alveolar epithelial cells (AECs) and vascular endothelial cells (VECs). Furthermore, IL-4- and IL13-induced M2 macrophage polarization was suppressed by PFD treatment in vitro, resulting in reductions in the release of arginase-1(ARG-1), chitinase 3-like 3 (YM-1) and TGF-β1. Notably, the PFD-induced inhibitory effects on M2 macrophage polarization were associated with downregulation of nuclear factor kappa-B (NF-κB) p50 activity. Additionally, PFD could significantly inhibit ionizing radiation-induced chemokine secretion in MLE-12 cells and consequently impair the migration of RAW264.7 cells. PFD could also eliminate TGF-β1 from M2 macrophages by attenuating the activation of TGF-β1/Smad3. Conclusion：PFD is a potential therapeutic agent to ameliorate fibrosis in RILF by reducing M2 macrophage infiltration and inhibiting the activation of TGF-β1/Smad3.

A hispanolone-derived diterpenoid inhibits M2-Macrophage polarization in vitro via JAK/STAT and attenuates chitin induced inflammation in vivo

2018 ◽  
Vol 154 ◽  
pp. 373-383 ◽  
Author(s):  
Lidia Jiménez-García ◽  
María Ángeles Higueras ◽  
Sandra Herranz ◽  
Marta Hernández-López ◽  
Alfonso Luque ◽  
...  
Keyword(s):  
Macrophage Polarization ◽  
M2 Macrophage ◽  
M2 Macrophage Polarization

scholarly journals Hexapeptide induces M2 macrophage polarization via the JAK1/STAT6 pathway to promote angiogenesis in bone repair

2021 ◽  
Author(s):  
Xinyun Han ◽  
Junxian Hu ◽  
Wenbo Zhao ◽  
Hongwei Lu ◽  
Jingjin Dai ◽  
...  
Keyword(s):  
Bone Repair ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Promising Alternative ◽  
Defect Repair ◽  
M2 Macrophage Polarization ◽  
Underlying Mechanisms ◽  
Main Regulator

Angiogenesis is essential for successful bone defect repair. In normal tissue repair, the physiological inflammatory response is the main regulator of angiogenesis through the activity of macrophages and the cytokines secreted by them. In particular, M2 macrophages which secrete high levels of PDGF-BB are typically considered to promote angiogenesis. A hexapeptide [WKYMVm, (Trp-Lys-Tyr-Met-Val-D-Met-NH2)] has been reported to modulate inflammatory activities. However, the underlying mechanisms by which WKYMVm regulates macrophages remain unclear. In this study, the possible involvement by which WKYMVm induces the polarization of macrophages and affects their behaviors was evaluated. In vitro results showed that macrophages were induced to an M2 rather than M1 phenotype and the M2 phenotype was enhanced by WKYMVm through activation of the JAK1/STAT6 signaling pathway. It was also found that WKYMVm played an important role in the PDGF-BB production increase and proangiogenic abilities in M2 macrophages. Consistent with the results in vitro, the elevated M2/M0 ratio induced by WKYMVm enhanced the formation of new blood vessels in a femoral defect mouse model. In summary, these findings suggest that WKYMVm could be a promising alternative strategy for angiogenesis in bone repair by inducing M2 macrophage polarization.

scholarly journals Ubiquitylation of MFHAS1 by the ubiquitin ligase praja2 promotes M1 macrophage polarization by activating JNK and p38 pathways

2017 ◽  
Vol 8 (5) ◽  
pp. e2763-e2763 ◽  
Author(s):  
Jing Zhong ◽  
Huihui Wang ◽  
Wankun Chen ◽  
Zhirong Sun ◽  
Jiawei Chen ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Toll Like Receptor ◽  
M1 Macrophage ◽  
M2 Macrophage Polarization ◽  
P38 Pathway

Abstract Sepsis is a systemic inflammation caused by infection. The balance between M1–M2 macrophage polarization has an essential role in the pathogenesis of sepsis. However, the exact mechanism underlying macrophage polarization is unclear. We previously showed that levels of malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) were significantly elevated in septic patients compared with those in nonseptic patients, and involved in the activation of Toll-like receptor (TLR) 2/c-Jun N-terminal kinase (JNK)/nuclear factor (NF)-κB pathway. In the present study, we explored whether MFHAS1 was involved in macrophage polarization and determined the effect of MFHAS1 on inflammation. We performed in vitro pulldown assays and in vivo co-immunoprecipitation assays and found that E3 ubiquitin ligase praja2 could directly bind to MFHAS1. In situ immunostaining analysis confirmed the colocalization of endogenous praja2 with MFHAS1. We first reported that praja2 promotes the accumulation of ubiquitylated MFHAS1 but does not degrade it. Moreover, our results indicate that MFHAS1 ubiquitylation by praja2 positively regulates TLR2-mediated JNK/p38 pathway and promotes M1 macrophage polarization, M2 to M1 macrophage transformation and inflammation.

scholarly journals Ovarian Cancer Cell-Derived Exosomal miR-205 Promotes M2 Macrophage Polarization and Ovarian Cancer Cell Metastasis By Activating The AKT/mTOR Signalling Pathway

2021 ◽  
Author(s):  
Liuqing He ◽  
Quan Chen ◽  
Di Wu ◽  
Wei Zhu ◽  
Qifeng Chen ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Ovarian Cancer Cell ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Qrt Pcr ◽  
M2 Macrophage Polarization

Abstract Background: Tumour-associated macrophages (TAMs) are the most abundant immune cells in the tumour environment and are considered to be similar to M2 macrophages, which facilitate cancer progression. Exosomes, as important mediators of cell-to-cell communication, can alter the phenotype of TAMs by transferring microRNAs (miRNAs) that influence targets and signalling pathways. However, the exact mechanisms by which cancer-derived exosomal miRNAs facilitate the development and metastasis of ovarian cancer (OC) remain unclear.Methods: In situ hybridization and immunohistochemistry were performed to examine the relationship between miR-205 and CD163 in OC. Exosome labelling experiments and qRT-PCR were used to detect the transfer of miR-205 from OC cells to macrophages. The effects of exosomal miR-205-induced macrophages on OC cell migration, invasion and EMT were assessed by in vitro assays in a co-culture model. Western blotting and qRT-PCR experiments were performed to investigate the role of the PI3K/AKT/mTOR axis in M2 macrophage polarization induced by exosomal miR-205. An in vivo mouse tumour model was used to evaluate the effects of M2 macrophages induced by exosomal miR-205.Results: We found that miR-205 expression levels were associated with M2 macrophage infiltration in patients with OC. miR-205 could be transported from OC cells to macrophages via exosomes and altered the macrophage phenotype. Moreover, macrophages that received exosomal miR-205 further enhanced the invasion, migration and EMT of OC cells. Decreased PTEN levels caused by exosomal miR-205 could increase the activation of AKT and mTOR as well as the expression of several immunosuppressive factors. In contrast, inhibition of miR-205 or restoration of PTEN effectively decreased cancer-mediated M2-type polarization, improving the infiltration of inflammatory factors in the tumour environment. Exosomal miR-205 derived from OC cells was found to induce M2-type polarization of macrophages and promote cancer progression in vivo.Conclusions: These results suggest a novel mechanism by which exosomal miR-205 induces M2 macrophage polarization and facilitates OC progression by targeting the PI3K/AKT/mTOR axis. Targeting exosomal miR-205 may offer a potential diagnosis and treatment strategy for OC.

scholarly journals Exosomal DLX6-AS1 from hepatocellular carcinoma cells induces M2 macrophage polarization to promote migration and invasion in hepatocellular carcinoma through microRNA-15a-5p/CXCL17 axis

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Lin-pei Wang ◽  
Jing Lin ◽  
Xiao-qiu Ma ◽  
Dong-yao Xu ◽  
Chun-feng Shi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Macrophage Polarization ◽  
Migration And Invasion ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Mesenchymal Transition ◽  
M2 Macrophage Polarization ◽  
Hcc Cells

Abstract Background Hepatocellular carcinoma (HCC) cells-secreted exosomes (exo) could stimulate M2 macrophage polarization and promote HCC progression, but the related mechanism of long non-coding RNA distal-less homeobox 6 antisense 1 (DLX6-AS1) with HCC-exo-mediated M2 macrophage polarization is largely ambiguous. Thereafter, this research was started to unearth the role of DLX6-AS1 in HCC-exo in HCC through M2 macrophage polarization and microRNA (miR)-15a-5p/C-X-C motif chemokine ligand 17 (CXCL17) axis. Methods DLX6-AS1, miR-15a-5p and CXCL17 expression in HCC tissues and cells were tested. Exosomes were isolated from HCC cells with overexpressed DLX6-AS1 and co-cultured with M2 macrophages. MiR-15a-5p/CXCL17 down-regulation assays were performed in macrophages. The treated M2 macrophages were co-cultured with HCC cells, after which cell migration, invasion and epithelial mesenchymal transition were examined. The targeting relationships between DLX6-AS1 and miR-15a-5p, and between miR-15a-5p and CXCL17 were explored. In vivo experiment was conducted to detect the effect of exosomal DLX6-AS1-induced M2 macrophage polarization on HCC metastasis. Results Promoted DLX6-AS1 and CXCL17 and reduced miR-15a-5p exhibited in HCC. HCC-exo induced M2 macrophage polarization to accelerate migration, invasion and epithelial mesenchymal transition in HCC, which was further enhanced by up-regulated DLX6-AS1 but impaired by silenced DLX6-AS1. Inhibition of miR-15a-5p promoted M2 macrophage polarization to stimulate the invasion and metastasis of HCC while that of CXCL17 had the opposite effects. DLX6-AS1 mediated miR-15a-5p to target CXCL17. DLX6-AS1 from HCC-exo promoted metastasis in the lung by inducing M2 macrophage polarization in vivo. Conclusion DLX6-AS1 from HCC-exo regulates CXCL17 by competitively binding to miR-15a-5p to induce M2 macrophage polarization, thus promoting HCC migration, invasion and EMT.

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