Exosomal microRNA let-7-5p from Taenia pisiformis Cysticercus Prompted Macrophage to M2 Polarization through Inhibiting the Expression of C/EBP δ

Cysticercus pisiformis, the larval stage of Taenia pisiformis, causes serious illness in rabbits that severely impacts the rabbit breeding industry. An inhibitive Th2 immune response can be induced by let-7-enriched exosomes derived from T. pisiformis cysticercus. However, the underlying molecular mechanisms are not completely understood. Here, we report that exosomal miR-let-7-5p released by T. pisiformis cysticercus played a critical role in the activation of M2 macrophages. We found that overexpression of let-7-5p in M1 macrophages decreased M1 phenotype expression while promoting polarization to the M2 phenotype, which is consistent with experimental data in exosome-treated macrophages alone. In contrast, knockdown of let-7-5p in exosome-like vesicles promoted M1 polarization and decreased M2 phenotype expression. Furthermore, down-regulation of transcription factor CCAAT/enhancer-binding protein (C/EBP)-δ resulted in the decrease of M1 phenotype markers and increase of M2 phenotype markers. These results suggested that let-7 enriched in exosome-like vesicles from T. pisiformis metacestodes can induce M2 macrophage polarization via targeting C/EBP δ, which may be involved in macrophage polarization induced by T. pisiformis metacestodes. The finding helps to expand our knowledge of the molecular mechanism of immunosuppression and Th2 immune response induced by metacestodes.

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871 In vitro immunoregulatory effect from cervical cancer derived mesenchymal stromal cells over molecules expression in monocyte derived macrophage polarization

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0871 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A923-A923

Author(s):

Víctor Cortés-Morales ◽

Juan Montesinos ◽

Luis Chávez-Sánchez ◽

Sandra Espíndola-Garibay ◽

Alberto Monroy-García ◽

...

Keyword(s):

Cervical Cancer ◽

Stem Cells ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Macrophage Polarization ◽

Induction Medium ◽

M2 Macrophage ◽

List Type ◽

M2 Phenotype

BackgroundMacrophages are immunological cells that sense microenvironmental signals that may result in the polarized expression of either proinflammatory (M1) or anti-inflammatory (M2) phenotype.1 Macrophages M2 are present in tumoral microenvironment and their presence in patients with cervical cancer (CeCa) is related with less survival.2Mesenchymal Stromal Cells (MSCs) are also present in tumor microenvironment of cervical cancer (CeCa-MSC), which have shown immunoregulatory effects over CD8 T cells, decreasing their cytotoxic effect against tumoral cells.3 Interestingly, MSCs from bone marrow (BM-MSC) decrease M1 and increase M2 macrophage polarization in an in vitro coculture system.4 Macrophages and MSCs are present in microenvironment of cervical cancer, however it is unknown if MSCs play a role in macrophage polarization. In the present study, we have evaluated the immunoregulatory capacity of CeCa-MSCs to induce macrophage polarization.MethodsCD14 monocytes were isolated from peripheral blood and cultivated in the absence or presence of MSCs from BM, normal cervix (NCx) and CeCa. Two culture conditions were included, in the presence of induction medium to favors M1 (GM-CSF, LPS and IFNg) or M2 (M-CSF, IL-4 and IL-13) macrophage polarization. M1 (HLA-DR, CD80, CD86 and IFNg) or M2 (CD14, CD163, CD206, IDO and IL-10) macrophage molecular markers were evaluated by flow cytometry. Finally, we evaluated concentration of IL-10 and TNFa in conditioned medium form all coculture conditions.ResultsWe observed that CeCa-MSCs and BM-MSCs in presence of M1 induction medium, decreased M1 macrophage markers (HLA-II, CD80, CD86 and IFNg), and increase the expression of CD14 (M2 macrophage marker). Interestingly, in presence of M2 induction medium, BM-MSCs and CaCe-MSCs but not CxN-MSC increased CD163, CD206, IDO and IL-10 (M2 macrophage markers). We observed a decreased concentration of TNFa in the supernatant medium from all cocultures with MSCs, but only in presence of CeCa-MSCs, increased IL-10 concentration was detected in such cocultures.ConclusionsIn contrast to NCx-MSCs, CeCa-MSCs similarly to BM-MSCs have in vitro capacity to decrease M1 and increase M2 macrophage phenotype.AcknowledgementsAcknowledgments The authors are indebted to gratefully acknowledge to CONACYT (Grant No. 272793) and IMSS (Grant no. 1731) for support to Juan J. Montesinos research.ReferencesMartinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 2014;6-13.Petrillo M, Zannoni GF, Martinelli E, et al. Polarization of tumor-associated macrophages toward M2 phenotype correlates with poor response to chemoradiation and reduced survival in patients with locally advanced cervical cancer. PLoS One 2015;10: e0136654.Montesinos JJ, Mora-García Mde L, et al. In vitro evidence of the presence of mesenchymal stromal cells in cervical cancer and their role in protecting cancer cells from cytotoxic T cell activity. Stem Cells Dev 2013;22:2508-2519.Vasandan AB, Jahnavi S, Shashank C. Human mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE 2-dependent mechanism. Sci Rep 2016;6:38308.

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

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.553 ◽

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.

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Dual-Wavelength Photosensitive Nano-in-Micro Scaffold Regulates Innate and Adaptive Immune Responses for Osteogenesis

Nano-Micro Letters ◽

10.1007/s40820-020-00540-z ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Qin Zhao ◽

Miusi Shi ◽

Chengcheng Yin ◽

Zifan Zhao ◽

Jinglun Zhang ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Immune Cells ◽

Inflammatory Responses ◽

Macrophage Polarization ◽

T Cell Response ◽

Dual Wavelength ◽

M2 Macrophage ◽

Adaptive Immune Responses ◽

Adaptive Immune

AbstractThe immune response of a biomaterial determines its osteoinductive effect. Although the mechanisms by which some immune cells promote regeneration have been revealed, the biomaterial-induced immune response is a dynamic process involving multiple cells. Currently, it is challenging to accurately regulate the innate and adaptive immune responses to promote osteoinduction in biomaterials. Herein, we investigated the roles of macrophages and dendritic cells (DCs) during the osteoinduction of biphasic calcium phosphate (BCP) scaffolds. We found that osteoinductive BCP directed M2 macrophage polarization and inhibited DC maturation, resulting in low T cell response and efficient osteogenesis. Accordingly, a dual-targeting nano-in-micro scaffold (BCP loaded with gold nanocage, BCP-GNC) was designed to regulate the immune responses of macrophages and DCs. Through a dual-wavelength photosensitive switch, BCP-GNC releases interleukin-4 in the early stage of osteoinduction to target M2 macrophages and then releases dexamethasone in the later stage to target immature DCs, creating a desirable inflammatory environment for osteogenesis. This study demonstrates that biomaterials developed to have specific regulatory capacities for immune cells can be used to control the early inflammatory responses of implanted materials and induce osteogenesis.

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The Degree of Helicobacter pylori Infection Affects the State of Macrophage Polarization through Crosstalk between ROS and HIF-1α

Oxidative Medicine and Cellular Longevity ◽

10.1155/2020/5281795 ◽

2020 ◽

Vol 2020 ◽

pp. 1-16

Author(s):

Ying Lu ◽

Jianfang Rong ◽

Yongkang Lai ◽

Li Tao ◽

Xiaogang Yuan ◽

...

Keyword(s):

Helicobacter Pylori ◽

Macrophage Polarization ◽

Polarization State ◽

Hypoxia Inducible Factor ◽

Mtor Pathway ◽

Raw 264.7 Cells ◽

Gastric Lesions ◽

M1 Phenotype ◽

H Pylori ◽

M2 Phenotype

Background and Objective. Helicobacter pylori (H. pylori) is involved in macrophage polarization, but the specific mechanism is not well understood. Therefore, this study is aimed at investigating the effects of the degree of H. pylori infection on the macrophage polarization state and the crosstalk between reactive oxygen species (ROS) and hypoxia-inducible factor 1 α (HIF-1α) in this process. Methods. The expression of CD86, CD206, and HIF-1α in the gastric mucosa was evaluated through immunohistochemistry. RAW 264.7 cells were cocultured with H. pylori at various multiplicities of infection (MOIs), and iNOS, CD86, Arg-1, CD206, and HIF-1α expression was detected by Western blot, PCR, and ELISA analyses. ROS expression was detected with the fluorescent probe DCFH-DA. Macrophages were also treated with the ROS inhibitor NAC or HIF-1α inhibitor YC-1. Results. Immunohistochemical staining revealed that the macrophage polarization state was associated with the progression of gastric lesions and state of H. pylori infection. The MOI of H. pylori affected macrophage polarization, and H. pylori enhanced the expression of ROS and HIF-1α in macrophages. A low MOI of H. pylori promoted both the M1 and M2 phenotypes, while a high MOI suppressed the M2 phenotype. Furthermore, ROS inhibition attenuated HIF-1α expression and switched macrophage polarization from M1 to M2. However, HIF-1α inhibition suppressed ROS expression and inhibited both the M1 phenotype and the M2 phenotype. Inhibition of ROS or HIF-1α also suppressed the activation of the Akt/mTOR pathway, which was implicated in H. pylori-induced macrophage polarization. Conclusions. Macrophage polarization is associated with the progression of gastric lesions and state of H. pylori infection. The MOI of H. pylori influences the macrophage polarization state. Crosstalk between ROS and HIF-1α regulates H. pylori-induced macrophage polarization via the Akt/mTOR pathway.

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Advanced Glycation End Products Enhance Macrophages Polarization into M1 Phenotype through Activating RAGE/NF-κB Pathway

BioMed Research International ◽

10.1155/2015/732450 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 49

Author(s):

Xian Jin ◽

Tongqing Yao ◽

Zhong’e Zhou ◽

Jian Zhu ◽

Song Zhang ◽

...

Keyword(s):

Advanced Glycation End Products ◽

Macrophage Polarization ◽

M2 Macrophage ◽

Advanced Glycation ◽

Alternatively Activated Macrophages ◽

M1 Macrophage ◽

Glycation End Products ◽

End Products ◽

Patients With Diabetes ◽

M1 Phenotype

Atherosclerotic lesions are accelerated in patients with diabetes. M1 (classically activated in contrast to M2 alternatively activated) macrophages play key roles in the progression of atherosclerosis. Since advanced glycation end products (AGEs) are major pathogenic factors and active inflammation inducers in diabetes mellitus, this study assessed the effects of AGEs on macrophage polarization. The present study showed that AGEs significantly promoted macrophages to express IL-6 and TNF-α. M1 macrophage markers such as iNOS and surface markers including CD11c and CD86 were significantly upregulated while M2 macrophage markers such as Arg1 and CD206 remained unchanged after AGEs stimulation. AGEs significantly increased RAGE expression in macrophages and activated NF-κB pathway, and the aforementioned effects were partly abolished by administration of anti-RAGE antibody or NF-κB inhibitor PDTC. In conclusion, our results suggest that AGEs enhance macrophage differentiation into proinflammatory M1 phenotype at least partly via RAGE/NF-κB pathway activation.

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MicroRNA-720 suppresses M2 macrophage polarization by targeting GATA3

Bioscience Reports ◽

10.1042/bsr20160105 ◽

2016 ◽

Vol 36 (4) ◽

Cited By ~ 21

Author(s):

Yan Zhong ◽

Chun Yi

Keyword(s):

Macrophage Polarization ◽

Ectopic Expression ◽

Tumour Microenvironment ◽

M2 Macrophage ◽

Breast Carcinomas ◽

Downstream Target ◽

M2 Polarization ◽

M2 Macrophage Polarization ◽

And Function ◽

M2 Phenotype

Macrophages are highly plastic cells with the ability to differentiate into both M1- and M2-polarized phenotypes. As a distinct M2-polarized population, tumour-associated macrophages (TAMs) promote tumorigenesis owing to their pro-angiogenic and immune-suppressive functions in tumour microenvironment. In the present study, we found that the microRNA-720 (miR-720) was down-regulated in TAMs isolated from breast carcinomas and M2-polarization macrophages. Overexpression of miR-720 attenuated M2 phenotype expression and thus inhibited M2 polarization. We further identified GATA binding protein 3 (GATA3), a transcriptional factor that plays an important role in M2 macrophage polarization, was the downstream target of miR-720. Ectopic expression of GATA3 restored the M2 phenotype in miR-720 overexpressed macrophages. Importantly, overexpression of miR-720 inhibited pro-migration behaviour and phagocytic ability of M2-polarized macrophages. Thus, our data suggest that miR-720 plays an important role in regulating M2 macrophage polarization and function.

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Magnetically-Targeted Nanoparticle-Guided M2 Macrophage Polarization For Fracture Healing Promotion

10.21203/rs.3.rs-779102/v1 ◽

2021 ◽

Author(s):

Wu Zhou ◽

Ze Lin ◽

Yuan Xiong ◽

Hang Xue ◽

Wen Song ◽

...

Keyword(s):

Fracture Healing ◽

Osteogenic Differentiation ◽

Silicon Nanoparticles ◽

Macrophage Polarization ◽

Osteoblastic Differentiation ◽

Fracture Site ◽

M2 Macrophage ◽

Mesoporous Silicon ◽

M2 Macrophage Polarization ◽

M2 Phenotype

Abstract Background: Macrophages are essential for fracture healing, acting mainly through remodeling of the extracellular matrix and promotion of angiogenesis. The role of macrophages in regulating osteogenic differentiation, particularly that of the M2 phenotype, is increasingly researched. Baicalein (BCL) had also been shown to have pro-fracture-healing effects.Results: In this study, we developed mesoporous silica and Fe3O4 composite-targeted nanoparticles loaded with BCL (BCL@MMSNPs-SS-CD-NW), that could be magnetically delivered to the fracture site. These induced macrophage recruitment in a targeted manner, polarizing them towards the M2 phenotype, and thereby inducing MSCs towards osteoblastic differentiation. The mesoporous silicon nanoparticles (MSNs) were prepared with surface sulfhydrylation and amination modification, and the mesoporous channels were blocked with β-cyclodextrin. The outer layer of the mesoporous silicon was added with an amantane-modified NW targeting peptide to obtain the targeted nano-system. After entering macrophages, BCL could be released from nanoparticles since the disulfide linker could be cleaved by intracellular glutathione (GSH) resulting in the removing of CD gatekeeper, which is a key element in the pro-bone-remodeling functions, such as anti-inflammation and induction of M2 macrophage polarization to facilitate osteogenic differentiation.Conclusions: This nano-system passively accumulated in the fracture site, promoting osteogenic differentiation activities, highlighting a potent therapeutic benefit with high biosafety.

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Harnessing the immune response to improve functional healing

Science Translational Medicine ◽

10.1126/scitranslmed.aav3889 ◽

2018 ◽

Vol 10 (463) ◽

pp. eaav3889 ◽

Cited By ~ 3

Author(s):

Julianne L. Holloway

Keyword(s):

Immune Response ◽

Gold Nanoparticles ◽

Mouse Model ◽

Macrophage Polarization ◽

Interleukin 4 ◽

M2 Macrophage ◽

Muscle Recovery ◽

M2 Macrophage Polarization

Interleukin-4–conjugated gold nanoparticles promote M2 macrophage polarization and functional muscle recovery in an ischemic mouse model.

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A Review of Macrophage MicroRNAs’ Role in Human Asthma

Cells ◽

10.3390/cells8050420 ◽

2019 ◽

Vol 8 (5) ◽

pp. 420 ◽

Cited By ~ 7

Author(s):

Gavriela Feketea ◽

Corina I Bocsan ◽

Cristian Popescu ◽

Mihaela Gaman ◽

Luminita A Stanciu ◽

...

Keyword(s):

Macrophage Polarization ◽

Critical Role ◽

Human Macrophage ◽

Published Data ◽

M2 Macrophage ◽

Macrophage Phenotype ◽

Activated Macrophages ◽

Novel Therapy ◽

Alternatively Activated Macrophages ◽

Classically Activated Macrophages

There is an imbalance in asthma between classically activated macrophages (M1 cells) and alternatively activated macrophages (M2 cells) in favor of the latter. MicroRNAs (miRNAs) play a critical role in regulating macrophage proliferation and differentiation and control the balance of M1 and M2 macrophage polarization, thereby controlling immune responses. Here we review the current published data concerning miRNAs with known correlation to a specific human macrophage phenotype and polarization, and their association with adult asthma. MiRNA-targeted therapy is still in the initial stages, but clinical trials are under recruitment or currently running for some miRNAs in other diseases. Regulating miRNA expression via their upregulation or downregulation could show potential as a novel therapy for improving treatment efficacy in asthma.

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Lung Tumor Cell-Derived Exosomes Promote M2 Macrophage Polarization

Cells ◽

10.3390/cells9051303 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1303 ◽

Cited By ~ 2

Author(s):

Alexandra Pritchard ◽

Sultan Tousif ◽

Yong Wang ◽

Kenneth Hough ◽

Saad Khan ◽

...

Keyword(s):

Bone Marrow ◽

Tumor Cells ◽

Bone Marrow Cells ◽

Lung Tumor ◽

Macrophage Polarization ◽

M2 Macrophage ◽

M2 Macrophages ◽

M2 Macrophage Polarization ◽

The Impact ◽

M2 Phenotype

Cellular cross-talk within the tumor microenvironment (TME) by exosomes is known to promote tumor progression. Tumor promoting macrophages with an M2 phenotype are suppressors of anti-tumor immunity. However, the impact of tumor-derived exosomes in modulating macrophage polarization in the lung TME is largely unknown. Herein, we investigated if lung tumor-derived exosomes alter transcriptional and bioenergetic signatures of M0 macrophages and polarize them to an M2 phenotype. The concentration of exosomes produced by p53 null H358 lung tumor cells was significantly reduced compared to A549 (p53 wild-type) lung tumor cells, consistent with p53-mediated regulation of exosome production. In co-culture studies, M0 macrophages internalized tumor-derived exosomes, and differentiated into M2 phenotype. Importantly, we demonstrate that tumor-derived exosomes enhance the oxygen consumption rate of macrophages, altering their bioenergetic state consistent with that of M2 macrophages. In vitro co-cultures of M0 macrophages with H358 exosomes demonstrated that exosome-induced M2 polarization may be p53 independent. Murine bone marrow cells and bone marrow-derived myeloid-derived suppressor cells (MDSCs) co-cultured with lewis lung carcinoma (LLC)-derived exosomes differentiated to M2 macrophages. Collectively, these studies provide evidence for a novel role for lung tumor-exosomes in M2 macrophage polarization, which then offers new therapeutic targets for immunotherapy of lung cancer.

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