(-)-Epigallocatechin-3-gallate (EGCG) modulates polarized macrophages to suppress M1 phenotype and promote M2 polarization in vitro and in vivo

Anti-angiogenic therapies for melanoma have not yet been translated into meaningful clinical benefit for patients, due to development of drug-induced resistance in cancer cells, mainly caused by hypoxia-inducible factor 1α (HIF-1α) overexpression and enhanced oxidative stress mediated by tumor-associated macrophages (TAMs). Our previous study demonstrated synergistic antitumor actions of simvastatin (SIM) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on an in vitro melanoma model via suppression of the aggressive phenotype of melanoma cells and inhibition of TAMs-mediated angiogenesis. Therefore, we took the advantage of long circulating liposomes (LCL) superior tumor targeting capacity to efficiently deliver SIM and DMXAA to B16.F10 melanoma in vivo, with the final aim of improving the outcome of the anti-angiogenic therapy. Thus, we assessed the effects of this novel combined tumor-targeted treatment on s.c. B16.F10 murine melanoma growth and on the production of critical markers involved in tumor development and progression. Our results showed that the combined liposomal therapy inhibited almost totally the growth of melanoma tumors, due to the enhancement of anti-angiogenic effects of LCL-DMXAA by LCL-SIM and induction of a pro-apoptotic state in the tumor microenvironment (TME). These effects were favoured by the partial re-education of TAMs towards a M1 phenotype and maintained via suppression of major invasion and metastasis promoters (HIF-1α, pAP-1 c-Jun, and MMPs). Thus, this novel therapy holds the potential to remodel the tumor microenvironment, by suppressing its most important malignant biological capabilities.

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Total Glucosides of Paeony Ameliorate Pristane-Induced Lupus Nephritis by Inducing PD-1 ligands+ Macrophages via Activating IL-4/STAT6/PD-L2 Signaling

Frontiers in Immunology ◽

10.3389/fimmu.2021.683249 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chun-Ling Liang ◽

Hongliang Jiang ◽

Wenxuan Feng ◽

Huazhen Liu ◽

Ling Han ◽

...

Keyword(s):

Lupus Nephritis ◽

Molecular Mechanisms ◽

Lavage Fluid ◽

Therapeutic Effects ◽

Raw264.7 Macrophages ◽

M2 Polarization ◽

Total Glucosides Of Paeony ◽

Radix Paeoniae Alba

Macrophages, a major subset of innate immune cells, are main infiltrating cells in the kidney in lupus nephritis. Macrophages with different phenotypes exert diverse or even opposite effects on the development of lupus nephritis. Substantial evidence has shown that macrophage M2 polarization is beneficial to individuals with chronic kidney disease. Further, it has been reported that PD-1 ligands (PD-Ls) contribute to M2 polarization of macrophages and their immunosuppressive effects. Total glucosides of paeony (TGP), originally extracted from Radix Paeoniae Alba, has been approved in China to treat some autoimmune diseases. Here, we investigated the potentially therapeutic effects of TGP on lupus nephritis in a pristane-induced murine model and explored the molecular mechanisms regulating macrophage phenotypes. We found that TGP treatment significantly improved renal function by decreasing the urinary protein and serum creatinine, reducing serum anti-ds-DNA level and ameliorating renal immunopathology. TGP increased the frequency of splenic and peritoneal F4/80+CD11b+CD206+ M2-like macrophages with no any significant effect on F4/80+CD11b+CD86+ M1-like macrophages. Immunofluorescence double-stainings of the renal tissue showed that TGP treatment increased the frequency of F4/80+Arg1+ subset while decreasing the percentage of F4/80+iNOS+ subset. Importantly, TGP treatment increased the percentage of both F4/80+CD11b+PD-L1+ and F4/80+CD11b+PD-L2+ subsets in spleen and peritoneal lavage fluid as well as the kidney. Furthermore, TGP augmented the expressions of CD206, PD-L2 and phosphorylated STAT6 in IL-4-treated Raw264.7 macrophages in vitro while its effects on PD-L2 were abolished by pretreatment of the cells with an inhibitor of STAT6, AS1517499. However, TGP treatment did not affect the expressions of STAT1 and PD-L1 in Raw264.7 macrophages treated with LPS/IFN-γ in vitro, indicating a possibly indirect effect of TGP on PD-L1 expression on macrophages in vivo. Thus, for the first time, we demonstrated that TGP may be a potent drug to treat lupus nephritis by inducing F4/80+CD11b+CD206+ and F4/80+CD11b+PD-L2+ macrophages through IL-4/STAT6/PD-L2 signaling pathway.

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A magnetic resonance nanoprobe with STING activation character collaborates with platinum-based drug for enhanced tumor immunochemotherapy

Journal of Nanobiotechnology ◽

10.1186/s12951-021-01158-y ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Jiali Li ◽

Shichao Li ◽

Yang Li ◽

Guanjie Yuan ◽

Yaqi Shen ◽

...

Keyword(s):

Magnetic Resonance ◽

Therapeutic Strategy ◽

Lung Epithelial Cells ◽

Mouse Lung ◽

Therapeutic Drugs ◽

Lung Epithelial ◽

M1 Phenotype ◽

Sting Pathway

Abstract Background Immunochemotherapy is a potent anti-tumor strategy, however, how to select therapeutic drugs to enhance the combined therapeutic effect still needs to be explored. Methods and results Herein, a magnetic resonance nanoprobe (MnP@Lip) with STING (Stimulator of INterferon Genes) activation character was synthesized and co-administered with platinum-based chemotherapeutics for enhanced immunochemotherapy. MnP@Lip nanoparticles was prepared by simple fabrication process with good reproducibility, pH-sensitive drug release behavior and biocompatibility. In vitro experiments elucidated that Mn2+ can promote the polarization of M0 and/or M2 macrophages to M1 phenotype, and promote the maturation of BMDC cells. Upon Mn2+ treatment, the STING pathway was activated in tumor cells, mouse lung epithelial cells, and immune cells. More importantly, anti-tumor experiments in vivo proved that MnP@Lip combined with platinum-based chemotherapeutics increased T cells infiltration in the tumor microenvironment, and inhibited tumor growth in the orthotopic therapeutic and postoperative tumor models. Conclusions This kind of therapeutic strategy that combined MnP@Lip nanoparticles with platinum-based chemotherapeutics may provide a novel insight for immunochemotherapy. Graphical Abstract

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Astrocyte Stimulates Microglial Proliferation and M2 Polarization in vitro through Cross-Talk between Astrocyte and Microglia

10.20944/preprints202107.0331.v1 ◽

2021 ◽

Author(s):

Sumin Kim ◽

Youngsook Son

Keyword(s):

Cross Talk ◽

Immune Functions ◽

Mixed Glial Culture ◽

Brain Functions ◽

M2 Polarization ◽

M2 Microglia ◽

Microglial Proliferation ◽

Stroke Mimic

Microglia are resident immune cells of the central nervous system such as brain-specific macrophages and also known to regulate the innate immune functions of astrocytes through secretory molecules. This conversation plays an important role in brain functions and homeostasis as well as in neuropathologic disease. In this study, we aimed to elucidate whether astrocytes and microglia can cross-talk to induce microglial polarization and proliferation, which can be further regulated under the brain stroke-mimic microenvironment. Microglia in mixed glial culture increased their survival and proliferation and altered to the M2 microglia, whose role was provided by CD11b-GFAP+ astrocytes by showing approximately tenfold increase in microglia cell proliferation after the astrocyte reconstitution. Furthermore, GM-CSF stimulated microglial proliferation approximately tenfold and induced to CCR7+ M1 microglia, whose phenotype could be suppressed by anti-inflammatory cytokines such as IL-4, IL-10, and Substance-P. Also, astrocyte in the microglia co-culture revealed A2 phenotype, which could be activated to A1 astrocyte by TNFα and IFNγ under the stroke-mimic condition. Altogether, astrocyte in the mixed glial culture stimulated the microglia proliferation and M2 polarization possibly through its acquisition of A2 phenotype, both of which could be converted to M1 microglia and A1 astrocytes under the inflammatory stroke-mimic environment. This study demonstrated that microglia and astrocyte can be polarized to M2 microglia and A2 astrocytes respectively through the cross-talk in vitro and provided a system to explore how microglia and astrocyte may behave in the inflammatory disease milieu after in vivo transplantation.

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Improved Promotion of M2 Microglial Polarization by Zuogui Jiangtang Jieyu Formulation in Diabetes-Related Depression

10.21203/rs.3.rs-335174/v1 ◽

2021 ◽

Author(s):

xiuli zhang ◽

Dahua Wu ◽

Dandan Li ◽

Jian Liu ◽

Chang Lei ◽

...

Keyword(s):

Inflammatory Cytokines ◽

High Glucose ◽

Neuroprotective Effect ◽

Enzyme Linked Immunosorbent Assay ◽

Mild Stress ◽

Microglial Polarization ◽

M2 Polarization ◽

M1 Polarization

Abstract Background Zuogui Jiangtang Jieyu formulation (ZGJTJY) is a Chinese polyherbal prescription for diabetes-related depression (DD). The mechanism underlying hippocampal M1/M2 polarization in DD and the ZGJTJY treatment effects remain unclear. This study aimed to investigate M1/M2 microglial polarization in the hippocampus of DD rats and HAPI (highly aggressively proliferating immortalized) cells simulating the DD state, as well as to examine the ZGJTJY intervention effects, both in vivo and in vitro. Methods We subjected Sprague Dawley rats to a high-fat diet, streptozotocin, and unpredictable chronic mild stress; subsequently, we orally administered ZGJTJY. HAPI cells were induced using high glucose and corticosterone; subsequently, ZGJTJY-containing serum was added to examine changes in M1/M2 microglial polarization. Moreover, metformin combined with fluoxetine (DMGB/F) was used as a positive drug for evaluating the ZGJTJY intervention. Laser confocal scanning was used to examine the microglial morphology. Further, real-time PCR was used to determine M1 markers (MHCII, iNOS, MCP-1, CD11b), M2 markers (Arg1, Mrc1, Ym1), pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and anti-inflammatory cytokines (IL-4, IL-10). Additionally, an enzyme-linked immunosorbent assay was used to examine inflammatory cytokines. Results There was significant activation of M1 polarization in the hippocampus of DD rats and HAPI cells induced using high glucose and corticosterone. Compared with DMGB/F, ZGJTJY inhibited and promoted M1 and M2 polarization, respectively; moreover, it decreased the M1-to-M2 polarization ratio both in vivo and in vitro. Conclusions The study indicated that hippocampal M1 polarization is crucially involved in DD pathogenesis; moreover, there is a need for further research on the neuroprotective effect of Chinese medicine associated with M2-polarized microglia.

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Gold nanoclusters conjugated berberine reduce inflammation and alleviate neuronal apoptosis by mediating M2 polarization for spinal cord injury repair

Regenerative Biomaterials ◽

10.1093/rb/rbab072 ◽

2021 ◽

Author(s):

Zipeng Zhou ◽

Dan Li ◽

Xiangyi Fan ◽

Yajiang Yuan ◽

Hongyu Wang ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Neuronal Apoptosis ◽

Gold Nanoclusters ◽

Protein Marker ◽

In Vivo Experiments ◽

Cord Injury ◽

M1 Phenotype

Abstract Spinal cord injury (SCI) leads to nerve cell apoptosis and loss of motor function. Herein, excessive activation of the M1 phenotype macrophages/microglia is found to be the main reason for the poor prognosis of SCI, but the selective activation phenotype (M2) macrophages/microglia facilitates the recovery of SCI. Thereafter, we used gold nanoclusters loaded berberine (BRB-AuNCs) to reduce inflammation by inhibiting the activation of M1 phenotype macrophages/microglia, which simultaneously inhibited neuronal apoptosis after SCI. In vitro and in vivo experiments showed that BRB-AuNCs reduced M1 protein marker CD86, increased M2 protein marker CD206, reduced inflammation and apoptotic cytokines (IL-1β, IL-6, TNF-α, Cleaved Caspase-3, Bax). These results indicate that BRB-AuNCs have excellent anti-inflammatory and anti-apoptotic effects by inducing the polarization of macrophages/microglia from M1 phenotype to M2 phenotype. Thereafter, the motor functions of SCI rats were significantly improved after treatment with BRB-AuNCs. This work not only provides a new way for the treatment of SCI but also broadens BRB utilization strategies.

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Correction to: In vitro and in vivo evaluation of anti‑tumoral effect of M1 phenotype induction in macrophages by miR‑130 and miR‑33 containing exosomes

Cancer Immunology Immunotherapy ◽

10.1007/s00262-020-02800-8 ◽

2020 ◽

Author(s):

Maryam Moradi-Chaleshtori ◽

Mojgan Bandehpour ◽

Sara Soudi ◽

Samira Mohammadi-Yeganeh ◽

Seyed Mahmoud Hashemi

Keyword(s):

In Vivo Evaluation ◽

M1 Phenotype

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Cordycepin Improved Neuronal Synaptic Plasticity Through CREB-Induced NGF Up-Regulation Driven By Microglial M2 Polarization: A Symphony Communication Between Microglia and Neurons in AD

10.21203/rs.3.rs-184003/v1 ◽

2021 ◽

Author(s):

Linchi Jiao ◽

Mingyan Liu ◽

Xin Zhong ◽

Weifan Yao ◽

Guowei Ma ◽

...

Keyword(s):

Synaptic Plasticity ◽

Animal Behavior ◽

Cell Biology ◽

Neuronal Apoptosis ◽

Microglial Activation ◽

Neuroprotective Effect ◽

M2 Polarization ◽

Improved Learning

Abstract Background: The purpose of this study was to explore the molecular mechanism of the neuroprotective effect of Cordycepin (CCS) on improving the neuro-immune microenvironment of AD neurons by mediating microglial M2 polarization. Methods: We investigated microglial M2 polarization from M1, neuronal senescence, and synaptic plasticity by biological techniques such as animal behavior, cell biology, morphology, and bioinformatics. Results: CCS improved learning and memory impairment in 9-month-old APP/PS1 mice. CCS induced the microglial M2 polarization, up-regulated the expression and secretion level of NGF, and inhibited neuronal apoptosis, senescence, and synaptic damage caused by abnormal microglial activation in vivo and in vitro. CREB was activated by the M2 polarization and mediated the NGF expression and secretion after CCS treatment. CREB bound with the Sg3 promoter region of NGF (-1018~-1011), which increased NGF expression and secretion. CREB-induced NGF upregulation driven by microglial M2 polarization to improve the neuronal synaptic plasticity inhibits neuronal apoptosis and senescence. As a novel participant in the intercellular communication between MG and neurons, NGF contributed to the neuroprotective efficacy of CCS treatment. Conclusions: CCS improved the neuronal synaptic plasticity and senescence by promoting microglial M2 activation driven by CERB-induced NGF upregulation and conducted the symphony communication of MG-Neuron in AD.

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Effect and Mechanism of Qingfei Paidu Decoction in the Management of Pulmonary Fibrosis and COVID-19

The American Journal of Chinese Medicine ◽

10.1142/s0192415x22500021 ◽

2021 ◽

pp. 1-19

Author(s):

Yu Wu ◽

Lili Xu ◽

Gang Cao ◽

Lingtian Min ◽

Tingting Dong

Keyword(s):

Pulmonary Fibrosis ◽

Epithelial Mesenchymal Transition ◽

Network Pharmacology ◽

Mesenchymal Transition ◽

Antifibrotic Therapy ◽

M2 Polarization ◽

Key Factor ◽

Novel Coronavirus

Qingfei Paidu decoction (QFPD) has been repeatedly recommended for the clinical treatment of novel coronavirus disease 2019 (COVID-19) in multiple provinces throughout China. A possible complication of COVID-19 lung involvement is pulmonary fibrosis, which causes chronic breathing difficulties and affects the patient’s quality of life. Therefore, there is an important question regarding whether QFPD can alleviate the process of pulmonary fibrosis and its potential mechanisms. To explore this issue, this study demonstrated the anti-pulmonary fibrosis activity and mode of action of QFPD in vivo and in vitro pulmonary fibrosis models and network pharmacology. The results showed that QFPD effectively ameliorated the bleomycin-induced inflammation and collagen deposition in mice and significantly improved the epithelial-mesenchymal transition in pulmonary fibrosis in mice. In addition, QFPD inhibited bleomycin-induced M2 polarization of macrophages in pulmonary tissues. An in-depth study of the mechanism of QFPD in the treatment of pulmonary fibrosis based on network pharmacology and molecular simulation revealed that SRC was the main target of QFPD and sitosterol (a key compound in QFPD). QFPD and sitosterol regulate the EMT process and M2 polarization of macrophages by inhibiting the activation of SRC, thereby alleviating pulmonary fibrosis in mice. COVID-19 infection might produce severe fibrosis, and antifibrotic therapy with QFPD may be valuable in preventing severe neocoronavirus disease in patients with IPF, which could be a key factor explaining the role of QFPD in the treatment of COVID-19.

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IL-4 Alleviates Ischaemia-Reperfusion Injury by Inducing Kupffer Cells M2 Polarization via STAT6-JMJD3 Pathway after Rat Liver Transplantation

BioMed Research International ◽

10.1155/2020/2953068 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12

Author(s):

Minghua Deng ◽

Jingyuan Wang ◽

Hao Wu ◽

Menghao Wang ◽

Ding Cao ◽

...

Keyword(s):

Liver Transplantation ◽

Reperfusion Injury ◽

Kupffer Cells ◽

Interleukin 4 ◽

Ischaemia Reperfusion Injury ◽

Ischaemia Reperfusion ◽

M2 Polarization ◽

Hepatocellular Apoptosis

Background. Liver ischaemia-reperfusion injury (IRI) remains a problem in liver transplantation. Interleukin-4 (IL-4) has been found to reduce liver IRI, but the exact mechanism remains unclear. Methods. Donor livers were infused with recombinant IL-4 or normal saline during cold storage, and the hepatocellular apoptosis and the inflammatory response were detected. The effect of IL-4 treatment on Kupffer cells (KCs) polarization and expression of the STAT6-JMJD3 pathway was evaluated in vivo and in vitro. KCs in donor livers were depleted by clodronate liposome treatment or JMJD3 was inhibited by GSK-J4 before liver transplantation to determine whether the protective effect of IL-4 treatment was dependent on KCs. Results. IL-4 treatment decreased sALT and sAST levels and alleviated hepatocellular apoptosis and inflammation at 6 h after liver transplantation. IL-4 treatment induced KCs alternatively activated (M2) polarization in vitro and in vivo, and the expression of STAT6 and JMJD3 was increased. JMJD3 knockdown abolished KCs M2 polarization and reduced the antiapoptotic and anti-inflammatory effects induced by IL-4 treatment in vitro. In addition, the protection of IL-4 treatment against IRI induced by liver transplantation was significantly reduced after the depletion of KCs or the inhibition of JMJD3 in donor livers. Conclusions. IL-4 treatment-induced KCs M2 polarization was dependent on the STAT6-JMJD3 pathway and protected liver grafts from IRI after liver transplantation.

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