BSA–MnO2–SAL multifunctional nanoparticle-mediated M1 macrophages polarization for glioblastoma therapy

Rheumatoid arthritis (RA) is characterized by the massive infiltration of various chronic inflammatory cells in synovia. In synovial fluid of patients with RA, M1 macrophages are dominant among all subtypes of macrophages, the mechanisms of macrophages polarization imbalance in RA has not been fully illuminated. The prostaglandin E2 (PGE2) augments M2 polarization in part via the cyclic adenosine monophosphate (cAMP)-cyclic AMP responsive element binding (CREB) signaling. However, previous study found constant stimulus of PGE2 on fibroblast-like synovial cells of adjuvant arthritis rats induced the decrease of cAMP, which is primarily caused by G protein-coupled receptor kinase 2 (GRK2)-induced EP4 over- desensitization. Whether GRK2 mediated-EP4 over-desensitization reduces the level of cAMP and inhibits M2 polarization in RA is unclear. Here we observed M1 macrophages were dominant in peritoneal macrophages (PMs), bone-marrow-derived macrophages (BMMs) and synovial macrophages of collagen-induced arthritis (CIA) mice. PGE2 stimulated M2 polarization via the EP4-cAMP-CREB in normal mice, while failed to promote M2 polarization in the PMs of CIA mice. Further, we found the EP4 over-desensitization stimulated by PGE2 induced abnormal PGE2-cAMP-CREB signaling as well as the imbalance of macrophage polarization. Targeted disruption of GRK2 in Raw264.7 (RAW) through GRK2 siRNA or CRISPR/Cas9 downregulated the M1 macrophage markers, upregulated the M2 macrophage markers and the EP4 membrane localization. The reduced M1/M2 ratio and increased p-CREB expression were observed in BMMs and PMs of GRK2+/− mice. This study highlighted a novel role of GRK2 in regulating macrophages function in RA and provided new idea for precision treatment of RA.

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Iron Released after Cryo-Thermal Therapy Induced M1 Macrophage Polarization, Promoting the Differentiation of CD4+ T Cells into CTLs

International Journal of Molecular Sciences ◽

10.3390/ijms22137010 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7010

Author(s):

Shicheng Wang ◽

Man Cheng ◽

Peng Peng ◽

Yue Lou ◽

Aili Zhang ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Antitumor Immunity ◽

Macrophage Polarization ◽

Thermal Therapy ◽

High Plasticity ◽

Antitumor Effects ◽

M1 Macrophages ◽

Splenic Macrophages ◽

M1 Macrophage

Macrophages play critical roles in both innate and adaptive immunity and are known for their high plasticity in response to various external signals. Macrophages are involved in regulating systematic iron homeostasis and they sequester iron by phagocytotic activity, which triggers M1 macrophage polarization and typically exerts antitumor effects. We previously developed a novel cryo-thermal therapy that can induce the mass release of tumor antigens and damage-associated molecular patterns (DAMPs), promoting M1 macrophage polarization. However, that study did not examine whether iron released after cryo-thermal therapy induced M1 macrophage polarization; this question still needed to be addressed. We hypothesized that cryo-thermal therapy would cause the release of a large quantity of iron to augment M1 macrophage polarization due to the disruption of tumor cells and blood vessels, which would further enhance antitumor immunity. In this study, we investigated iron released in primary tumors, the level of iron in splenic macrophages after cryo-thermal therapy and the effect of iron on macrophage polarization and CD4+ T cell differentiation in metastatic 4T1 murine mammary carcinoma. We found that a large amount of iron was released after cryo-thermal therapy and could be taken up by splenic macrophages, which further promoted M1 macrophage polarization by inhibiting ERK phosphorylation. Moreover, iron promoted DC maturation, which was possibly mediated by iron-induced M1 macrophages. In addition, iron-induced M1 macrophages and mature DCs promoted the differentiation of CD4+ T cells into the CD4 cytolytic T lymphocytes (CTL) subset and inhibited differentiation into Th2 and Th17 cells. This study explains the role of iron in cryo-thermal therapy-induced antitumor immunity from a new perspective.

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Cervus nippon var. mantchuricus water extract treated with digestive enzymes (CE) modulates M1 macrophage polarization through TLR4/MAPK/NF-κB signaling pathways on murine macrophages

European Journal of Inflammation ◽

10.1177/20587392211000898 ◽

2021 ◽

Vol 19 ◽

pp. 205873922110008

Author(s):

Se Hyang Hong ◽

Jin Mo Ku ◽

Ye Seul Lim ◽

Hyo In Kim ◽

Yong Cheol Shin ◽

...

Keyword(s):

Digestive Enzymes ◽

Macrophage Polarization ◽

Water Extract ◽

Cervus Nippon ◽

No Production ◽

M1 Macrophages ◽

Murine Macrophages ◽

M1 Macrophage ◽

Tnf Α ◽

Cytokine Levels

The objective of this study was to investigate the effects of Cervus nippon var. mantchuricus water extract treated with digestive enzymes (CE) on the promotion of M1 macrophage polarization in murine macrophages. Macrophages polarize either to one phenotype after stimulation with LPS or IFN-γ or to an alternatively activated phenotype that is induced by IL-4 or IL-13. Cell viability of RAW264.7 cells was determined by WST-1 assay. NO production was measured by Griess assay. IL-6, IL-12, TNF-α, and iNOS mRNA levels were measured by RT-PCR. IL-6, IL-12, and IL-10 cytokine levels were determined by ELISA. TLR4/MAPK/NF-κB signaling in RAW264.7 cells was evaluated by western blotting. The level of NF-κB was determined by immunoblotting. CE induced the differentiation of M1 macrophages. CE promoted M1 macrophages to elevate NO production and cytokine levels. CE-stimulated M1 macrophages had enhanced IL-6, IL-12, and TNF-α. CE promoted M1 macrophages to activate TLR4/MAPK/NF-κB phosphorylation. M2 markers were downregulated, while M1 markers were upregulated in murine macrophages by CE. Consequently, CE has immunomodulatory activity and can be used to promote M1 macrophage polarization through the TLR4/MAPK/NF-κB signaling pathways.

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DA-DRD5 signaling controls colitis by regulating colonic M1/M2 macrophage polarization

Cell Death and Disease ◽

10.1038/s41419-021-03778-6 ◽

2021 ◽

Vol 12 (6) ◽

Author(s):

Lu Liu ◽

Yuqing Wu ◽

Bingwei Wang ◽

Yuying Jiang ◽

Lin Lin ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

Macrophage Polarization ◽

Experimental Colitis ◽

M2 Macrophage ◽

M1 Macrophages ◽

Inflammatory Bowel ◽

M2 Macrophage Polarization ◽

Mechanistic Basis ◽

Functional Relevance ◽

Creb Pathway

AbstractThe decrease of neurotransmitter dopamine (DA) levels in the intestine is closely related to the development of inflammatory bowel disease (IBD). However, the functional relevance and underlying mechanistic basis of the effects of DA signaling on IBD remains unclear. Here, we observed that the DRD5 receptor is highly expressed in colonic macrophages, and the deficiency of DA-DRD5 signaling exacerbated experimental colitis. Moreover, DA-DRD5 signaling can inhibit M1 by negatively regulating NF-κB signaling but promote M2 macrophage polarization through activation of the CREB pathway, respectively. The deficiency of DRD5 signaling increased colonic M1 macrophages but reduced M2 cells during colitis. Additionally, the administration of a D1-like agonist that has a higher affinity to DRD5 can attenuate the colitogenic phenotype of mice. Collectively, these findings provide the first demonstration of DA-DRD5 signaling in colonic macrophages controlling the development of colitis by regulating M1/M2 macrophage polarization.

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Cancer Derived Exosomes Induce Macrophages Immunosuppressive Polarization to Promote Bladder Cancer Progression

10.21203/rs.3.rs-342320/v1 ◽

2021 ◽

Author(s):

Ziming Jiang ◽

Yiming Zhang ◽

Yu Zhang ◽

Zhankui Jia ◽

Zhengguo Zhang ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Progression ◽

Macrophage Polarization ◽

Tumor Model ◽

Tumor Xenograft ◽

Potential Therapeutic Target ◽

Macrophages Polarization ◽

Exosomal Mirnas ◽

Bladder Cancer Cells ◽

And Function

Abstract Background: Exosomes mediated crosstalk between tumor cells and other stromal cells including tumor associated macrophages (TAM) plays an essential role in reprogramming tumor microenvironment (TME) to facilitate tumor progression. However, the mechanism of tumor derived exosomes promotes bladder cancer progression have not been defined.Methods: Exosomes were extracted from bladder cancer cells MB49 conditioned medium by ultracentrifugation. The effects of MB49-derived exosomes on macrophages polarization were analyzed by qPCR, flow cytometry, and Western blot. The immunosuppressive phenotype and function of MB49-derived exosomes stimulated macrophages were verified by tumor xenograft assays and T cell co-culture experiments. Exosomal miRNAs were analyzed by microarray to identify potential targets regulating macrophage polarization.Results: MB49-derived exosomes could be ingested by macrophages, consequently promoting macrophages immunosuppressive polarization. Mechanically, the MB49-derived exosomes induced macrophage M2 polarization was mediated by down-regulation of PTEN and activation of AKT/STAT3/6 signaling. Moreover, hindrance of the generation or secretion of exosomes by GW4869 inhibited macrophages differentiation into immunosuppressive phenotype and function, thereby suppressed tumor growth in a mouse subcutaneous tumor model.Conclusion: Our study confirmed the contribution of bladder cancer derived exosomes on the establishment of immunosuppressive TME and provided a potential therapeutic target for bladder cancer treatment.

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LncRNA NRON alleviates atrial fibrosis through suppression of M1 macrophages activated by atrial myocytes

Bioscience Reports ◽

10.1042/bsr20192215 ◽

2019 ◽

Vol 39 (11) ◽

Cited By ~ 5

Author(s):

Fei Sun ◽

Zhixiang Guo ◽

Chengxin Zhang ◽

Hong Che ◽

Wenhui Gong ◽

...

Keyword(s):

Macrophage Polarization ◽

Underlying Mechanism ◽

Enzyme Linked Immunosorbent Assay ◽

Ang Ii ◽

Atrial Myocytes ◽

Atrial Fibrosis ◽

M1 Macrophages ◽

Protein Levels ◽

Raw264.7 Macrophages ◽

Non Coding Rna

Abstract The aim of the present study was to explore the role of long non-coding RNA (lncRNA) non-coding repressor of NFAT (NRON) in the atrial fibrosis and to explore whether its underlying mechanism was associated with macrophage polarization. Enzyme-linked immunosorbent assay (ELISA) analysis of pro-inflammatory cytokines revealed that NRON overexpression suppressed, whereas NRON silencing facilitated the angiotensin II (Ang II)-induced inflammatory response in primary cultured atrial myocytes. The chromatin immunoprecipitation (ChIP) results showed that nuclear factor of activated T cell 3 (NFATc3) was recruited to the promoter region of interleukin (IL) 12 (IL-12) in atrial myocytes. Further data showed that NRON overexpression suppressed, whereas NRON silencing further promoted the Ang II-induced NFATc3 nuclear transport and IL-12 expression in atrial myocytes. Moreover, RAW264.7 macrophages were incubated with the conditioned medium from the Ang II-treated atrial myocytes transfected with NRON and IL-12 overexpression vectors. IL-12 overexpression abrogated the NRON overexpression-mediated inhibition of RAW264.7 macrophage polarization to the M1-like phenotype. Additionally, mouse atrial fibroblasts were incubated with the culture medium from RAW264.7 macrophages treated as described above. IL-12 overexpression rescued the NRON overexpression-inhibited protein levels of fibrosis markers Collagen I/III in mouse atrial fibroblasts. Collectively, our data indicate that lncRNA NRON alleviates atrial fibrosis through suppression of M1 macrophages activated by atrial myocytes.

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Giant cell tumor stromal cells: osteoblast lineage-derived cells secrete IL-6 and IL-10 for M2 macrophages polarization

PeerJ ◽

10.7717/peerj.9748 ◽

2020 ◽

Vol 8 ◽

pp. e9748

Author(s):

Kuan Yang ◽

Lihui Bao ◽

Xiaoning He ◽

Wanmin Zhao ◽

Dongdong Fei ◽

...

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Stromal Cells ◽

Macrophage Polarization ◽

Giant Cells ◽

Interleukin 10 ◽

Cell Tumor ◽

M2 Macrophages ◽

M2 Polarization ◽

Macrophages Polarization

Background The giant cell tumor (GCT) is a benign tumor which consists of three types cells: mononuclear histiocytic cells (MNHCs), multinuclear giant cells (MNGCs), and GCT stromal cells (GCTSCs). Numerous studies claim that GCTSCs have mesenchymal stem cells (MSCs) characters and play an important role in osteoclastogenesis; however, there are no research studies concerning macrophage polarization among GCT, which can be regarded as an ingredient for tumor aggression. Method We tested the effect of GCTSCs from three GCT samples which were collected from patients on proliferation, apoptosis and polarization of macrophage. Result In this article, we verified that GCTSCs expressed MSCs markers and had higher proliferation and relative lower differentiation abilities compared with BMMSCs. What’s more, we found a higher proportion of M2 macrophages among neoplasm. Co-culturing GCTSCs with macrophages resulted in prominent macrophage M2 polarization and increased the release of IL-6 (Interleukin-6) and IL-10 (Interleukin-10)from GCTSCs. In conclusion, GCTSCs, as originating from MSCs, can secret IL-6 and IL-10, which may play a significant role in macrophage M2 polarization.

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Effect of Propofol on the Production of Inflammatory Cytokines by Human Polarized Macrophages

Mediators of Inflammation ◽

10.1155/2019/1919538 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 8

Author(s):

Tsukasa Kochiyama ◽

Xiaojia Li ◽

Hitoshi Nakayama ◽

Madoka Kage ◽

Yui Yamane ◽

...

Keyword(s):

Nuclear Translocation ◽

Inflammatory Responses ◽

Macrophage Polarization ◽

Signal Transduction Pathway ◽

Induce Polarization ◽

Human Macrophage ◽

Related Factor ◽

M2 Macrophages ◽

M1 Macrophages ◽

Inflammatory Processes

Macrophages are key immune system cells involved in inflammatory processes. Classically activated (M1) macrophages are characterized by strong antimicrobicidal properties, whereas alternatively activated (M2) macrophages are involved in wound healing. Severe inflammation can induce postoperative complications during the perioperative period. Invasive surgical procedures induce polarization to M1 macrophages and associated complications. As perioperative management, it is an important strategy to regulate polarization and functions of macrophages during inflammatory processes. Although propofol has been found to exhibit anti-inflammatory activities in monocytes and macrophages, it is unclear whether propofol regulates the functions of M1 and M2 macrophages during inflammatory processes. This study therefore investigated the effects of propofol on human macrophage polarization. During M1 polarization, propofol suppressed the production of IL-6 and IL-1β but did not affect TNF-α production. In contrast, propofol did not affect the gene expression of M2 markers, such as IL-10, TGF-β, and CD206, during M2 polarization. Propofol was similar to the GABAA agonist muscimol in inducing nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) and inhibiting IL-6 and IL-1β, but not TNF-α, production. Knockdown of Nrf2 using siRNA significantly reduced the effect of propofol on IL-6 and IL-1β production. These results suggest that propofol prevents inflammatory responses during polarization of human M1 macrophages by suppressing the expression of IL-6 and IL-1β through the GABAA receptor and the Nrf2-mediated signal transduction pathway.

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Glycyrrhizic Acid Promotes M1 Macrophage Polarization in Murine Bone Marrow-Derived Macrophages Associated with the Activation of JNK and NF-κB

Mediators of Inflammation ◽

10.1155/2015/372931 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 21

Author(s):

Yulong Mao ◽

Baikui Wang ◽

Xin Xu ◽

Wei Du ◽

Weifen Li ◽

...

Keyword(s):

Bone Marrow ◽

Glycyrrhizic Acid ◽

Macrophage Polarization ◽

Herbal Medicines ◽

Cell Surface Expression ◽

M2 Macrophage ◽

M1 Macrophages ◽

Murine Bone Marrow ◽

E Coli ◽

M1 Macrophage

The roots and rhizomes ofGlycyrrhizaspecies (licorice) have been widely used as natural sweeteners and herbal medicines. The aim of this study is to investigate the effect of glycyrrhizic acid (GA) from licorice on macrophage polarization. Both phenotypic and functional activities of murine bone marrow-derived macrophages (BMDMs) treated by GA were assessed. Our results showed that GA obviously increased the cell surface expression of CD80, CD86, and MHCII molecules. Meanwhile, GA upregulated the expression of CCR7 and the production of TNF-α, IL-12, IL-6, and NO (the markers of classically activated (M1) macrophages), whereas it downregulated the expression of MR, Ym1, and Arg1 (the markers of alternatively activated (M2) macrophage). The functional tests showed that GA dramatically enhanced the uptake of FITC-dextran andE. coliK88 by BMDMs and decreased the intracellular survival ofE. coliK88 andS. typhimurium. Moreover, we demonstrated that JNK and NF-κB activation are required for GA-induced NO and M1-related cytokines production, while ERK1/2 pathway exhibits a regulatory effect via induction of IL-10. Together, these findings indicated that GA promoted polarization of M1 macrophages and enhanced its phagocytosis and bactericidal capacity. The results expanded our knowledge about the role of GA in macrophage polarization.

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Iron Reduces M1 Macrophage Polarization in RAW264.7 Macrophages Associated with Inhibition of STAT1

Mediators of Inflammation ◽

10.1155/2017/8570818 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 21

Author(s):

Zhen-Shun Gan ◽

Qian-Qian Wang ◽

Jia-Hui Li ◽

Xu-Liang Wang ◽

Yi-Zhen Wang ◽

...

Keyword(s):

Iron Metabolism ◽

Iron Homeostasis ◽

Macrophage Polarization ◽

Reticuloendothelial System ◽

Molecular Signature ◽

Mrna Levels ◽

M1 Macrophages ◽

Iron Storage ◽

Raw264.7 Macrophages ◽

M1 Macrophage

Iron metabolism in inflammation has been mostly characterized in macrophages exposed to pathogens or inflammatory conditions. The aim of this study is to investigate the cross-regulatory interactions between M1 macrophage polarization and iron metabolism. Firstly, we characterized the transcription of genes related to iron homeostasis in M1 RAW264.7 macrophages stimulated by IFN-γ. The molecular signature of M1 macrophages showed high levels of iron storage (ferritin), a low level of iron export (ferroportin), and changes of iron regulators (hepcidin and transferrin receptors), which favour iron sequestration in the reticuloendothelial system and are benefit for inflammatory disorders. Then, we evaluated the effect of iron on M1 macrophage polarization. Iron significantly reduced mRNA levels of IL-6, IL-1β, TNF-α, and iNOS produced by IFN-γ-polarized M1 macrophages. Immunofluorescence analysis showed that iron also reduced iNOS production. However, iron did not compromise but enhanced the ability of M1-polarized macrophages to phagocytose FITC-dextran. Moreover, we demonstrated that STAT1 inhibition was required for reduction of iNOS and M1-related cytokines production by the present of iron. Together, these findings indicated that iron decreased polarization of M1 macrophages and inhibited the production of the proinflammatory cytokines. The results expanded our knowledge about the role of iron in macrophage polarization.

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