Hypoxia Pre-Challenged Glioma-Derived Exosomes Promote Recovery From Spinal Cord Injury by Inducing M2 Macrophage Polarization via Modulating MicroRNA-1246/TERF2IP and Let-7b/TERF2IP Signaling Pathway

Abstract Background: Hypoxic GLIOMA derived exosomes may induce M2 macrophage polarization by upregulating TERF2IP expression. Furthermore, M2 macrophage polarization was found to be associated with accelerated SCI recovery by suppressing inflammatory response. The underlying mechanism of the therapeutic role of hypoxic GLIOMA derived exosomes in SCI recovery remains to be explored.Methods: Electron microscopy and Western blot were used to characterize U251 derived exosomes. Quantitative real-time PCR was performed to measure the mRNA expression of target genes, and Western blot and IHC were used to evaluate the protein expression of target genes. ELISA was performed to examine the levels of cytokines. Luciferase assay was carried out to explore the inhibitory role of miR-1246/let-7b in the expression of TERF2IP. TUNEL was performed to evaluate the apoptosis of spinal cord cells in SCI rats. Results: Hypoxic U251 derived exosomes significantly enhanced the expression of CD163, IL-10, IL-1RA, TGFB1, and CCL2 as well as the proportion of CD11b+/CD163+ cells while suppressing the expression of TNFa in U937 cells. Furthermore, the expression of miR-1246 and let-7b was remarkably elevated by Hypoxic U251 derived exosomes, while the expression of TERF2IP was inhibited. Luciferase assay demonstrated that miR-1246/let-7b effectively suppressed the expression of TERF2IP through binding to its 3’ UTR. In an SCI rat model, hypoxic U251 derived exosomes notably promoted the survival and functional recovery of left hindlimb by up-regulating IL-10, miR-1246, and let-7b expression while down-regulating TNFa/TERF2IP expression and attenuating apoptosis of spinal cord cells.Conclusion: The findings of this study demonstrated that glioma derived exosomes upregulated the expression of miR-1246 and let-7b to suppress the expression of TERF2IP to induce M2 macrophage polarization. The promoted M2 macrophage polarization suppressed inflammatory response to accelerate the recovery from SCI.

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Local Injection of Lenti–BDNF at the Lesion Site Promotes M2 Macrophage Polarization and Inhibits Inflammatory Response After Spinal Cord Injury in Mice

Cellular and Molecular Neurobiology ◽

10.1007/s10571-015-0182-x ◽

2015 ◽

Vol 35 (6) ◽

pp. 881-890 ◽

Cited By ~ 34

Author(s):

Xin-Chao Ji ◽

Yuan-Yuan Dang ◽

Hong-Yan Gao ◽

Zhao-Tao Wang ◽

Mou Gao ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Inflammatory Response ◽

Macrophage Polarization ◽

Local Injection ◽

M2 Macrophage ◽

Lesion Site ◽

Cord Injury ◽

M2 Macrophage Polarization

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Bone marrow mesenchymal stem cell-derived exosomal microRNA-125a promotes M2 macrophage polarization in spinal cord injury by downregulating IRF5

Brain Research Bulletin ◽

10.1016/j.brainresbull.2021.02.015 ◽

2021 ◽

Vol 170 ◽

pp. 199-210

Author(s):

Qing Chang ◽

Yupeng Hao ◽

Yifan Wang ◽

Yingjie Zhou ◽

Hanjie Zhuo ◽

...

Keyword(s):

Spinal Cord ◽

Bone Marrow ◽

Spinal Cord Injury ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Macrophage Polarization ◽

M2 Macrophage ◽

Cord Injury ◽

M2 Macrophage Polarization ◽

Exosomal Microrna

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Cholesterol-Ester Transfer Protein Alters M1 and M2 Macrophage Polarization and Worsens Experimental Elastase-Induced Pulmonary Emphysema

Frontiers in Immunology ◽

10.3389/fimmu.2021.684076 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kelly Gomes Santana ◽

Renato Fraga Righetti ◽

Cristiane Naffah de Souza Breda ◽

Omar Alberto Domínguez-Amorocho ◽

Theresa Ramalho ◽

...

Keyword(s):

Bone Marrow ◽

Inflammatory Response ◽

Pulmonary Emphysema ◽

Cholesterol Ester ◽

Macrophage Polarization ◽

Cholesterol Ester Transfer Protein ◽

M2 Macrophage ◽

Transfer Protein ◽

M2 Macrophage Polarization

Cholesterol-ester transfer protein (CETP) plays a role in atherosclerosis, the inflammatory response to endotoxemia and in experimental and human sepsis. Functional alterations in lipoprotein (LP) metabolism and immune cell populations, including macrophages, occur during sepsis and may be related to comorbidities such as chronic obstructive pulmonary disease (COPD). Macrophages are significantly associated with pulmonary emphysema, and depending on the microenvironment, might exhibit an M1 or M2 phenotype. Macrophages derived from the peritoneum and bone marrow reveal CETP that contributes to its plasma concentration. Here, we evaluated the role of CETP in macrophage polarization and elastase-induced pulmonary emphysema (ELA) in human CETP-expressing transgenic (huCETP) (line 5203, C57BL6/J background) male mice and compared it to their wild type littermates. We showed that bone marrow-derived macrophages from huCETP mice reduce polarization toward the M1 phenotype, but with increased IL-10. Compared to WT, huCETP mice exposed to elastase showed worsened lung function with an increased mean linear intercept (Lm), reflecting airspace enlargement resulting from parenchymal destruction with increased expression of arginase-1 and IL-10, which are M2 markers. The cytokine profile revealed increased IL-6 in plasma and TNF, and IL-10 in bronchoalveolar lavage (BAL), corroborating with the lung immunohistochemistry in the huCETP-ELA group compared to WT-ELA. Elastase treatment in the huCETP group increased VLDL-C and reduced HDL-C. Elastase-induced pulmonary emphysema in huCETP mice promotes lung M2-like phenotype with a deleterious effect in experimental COPD, corroborating the in vitro result in which CETP promoted M2 macrophage polarization. Our results suggest that CETP is associated with inflammatory response and influences the role of macrophages in COPD.

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The inflammatory response to a wheelchair half-marathon in people with a spinal cord injury - the role of autonomic function

Journal of Sports Sciences ◽

10.1080/02640414.2019.1586296 ◽

2019 ◽

Vol 37 (15) ◽

pp. 1717-1724

Author(s):

Sven P. Hoekstra ◽

Christof A. Leicht ◽

Yoshi-Ichiro Kamijo ◽

Tokio Kinoshita ◽

Ben T. Stephenson ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Inflammatory Response ◽

Autonomic Function ◽

Cord Injury

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CCL3 contributes to secondary damage after spinal cord injury

Journal of Neuroinflammation ◽

10.1186/s12974-020-02037-3 ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Nicolas Pelisch ◽

Jose Rosas Almanza ◽

Kyle E. Stehlik ◽

Brandy V. Aperi ◽

Antje Kroner

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Inflammatory Response ◽

Lesion Size ◽

Secondary Injury ◽

Wild Type ◽

Locomotor Recovery ◽

Secondary Damage ◽

Cord Injury

Abstract Background Secondary damage after spinal cord injury (SCI) is characterized by a cascade of events including hemorrhage, apoptosis, oxidative stress, and inflammation which increase the lesion size which can influence the functional impairment. Thus, identifying specific mechanisms attributed to secondary injury is critical in minimizing tissue damage and improving neurological outcome. In this work, we are investigating the role of CCL3 (macrophage inflammatory protein 1-α, MIP-1α), a chemokine involved in the recruitment of inflammatory cells, which plays an important role in inflammatory conditions of the central and peripheral nervous system. Methods A mouse model of lower thoracic (T11) spinal cord contusion injury was used. We assessed expression levels of CCL3 and its receptors on the mRNA and protein level and analyzed changes in locomotor recovery and the inflammatory response in the injured spinal cord of wild-type and CCL3−/− mice. Results The expression of CCL3 and its receptors was increased after thoracic contusion SCI in mice. We then examined the role of CCL3 after SCI and its direct influence on the inflammatory response, locomotor recovery and lesion size using CCL3−/− mice. CCL3−/− mice showed mild but significant improvement of locomotor recovery, a smaller lesion size and reduced neuronal damage compared to wild-type controls. In addition, neutrophil numbers as well as the pro-inflammatory cytokines and chemokines, known to play a deleterious role after SCI, were markedly reduced in the absence of CCL3. Conclusion We have identified CCL3 as a potential target to modulate the inflammatory response and secondary damage after SCI. Collectively, this study shows that CCL3 contributes to progressive tissue damage and functional impairment during secondary injury after SCI.

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MicroRNA-146a Contributes to SCI Recovery via Regulating TRAF6 and IRAK1 Expression

BioMed Research International ◽

10.1155/2016/4013487 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Jinsong Wei ◽

Jiafeng Wang ◽

Yulan Zhou ◽

Shouquan Yan ◽

Keshen Li ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Rat Model ◽

Proinflammatory Cytokine ◽

Target Genes ◽

Sham Group ◽

Luciferase Assay ◽

Tight Control ◽

Cord Injury ◽

Novel Therapeutic

MicroRNA-146a participates in spinal cord injury (SCI) recovery. Until recently, how miRNA-146a participates in SCI remained unclear. In this study, we tried to explore the roles of miRNA-146a in the recovery of SCI using a rat model. The expression of the probable target genes of miRNA-146a (including IRAK1 and TARF6) as well as proinflammation cytokines were measured until 7 days after surgery in the three groups (sham group, SCI group, and miRNA-146a antagomir injection group). Also, the animals’ motivations were estimated using Basso Beattie Bresnahan (BBB) during the whole experiment. A luciferase assay was performed to demonstrate that miRNA-146a could directly target the mRNAs of IRAK1 and TRAF6. Our experiments indicate that miRNA-146a inhibits proinflammatory cytokine secretion by suppressing IRAK1 and TRAF6 expression in the SCI model. In contrast, miRNA-146a may be upregulated by inflammatory mediators via the IRAK1/TRAF6 pathway in the spinal cord. As a negative feedback element, miRNA-146a could make sure that the expression of IRAK1- and TRAF6-mediated genes was under tight control. Thus, miRNA-146a may serve as a novel therapeutic target for SCI interventions.

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MiR-520a-3p Inhibited Macrophage Polarization and Promoted the Development of Atherosclerosis via Targeting UVRAG in Apolipoprotein E Knockout Mice

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2020.621324 ◽

2021 ◽

Vol 7 ◽

Author(s):

Jing Rui Qi ◽

Dian Ru Zhao ◽

Li Zhao ◽

Fan Luo ◽

Mei Yang

Keyword(s):

Macrophage Polarization ◽

M2 Macrophage ◽

Treatment Target ◽

Vessel Disease ◽

Novel Treatment ◽

M1 Macrophage ◽

Apolipoprotein E Knockout Mice ◽

The World ◽

M2 Macrophage Polarization

Atherosclerosis (AS), a kind of chronic inflammatory blood vessel disease, is a main cause of cardiovascular disease, which is a leading cause of mortality around the world. Accumulation of macrophages induced by inflammation contributes to AS development. It has been indicated that microRNAs (miRNAs) are involved in the process of AS. However, the pathway and gene miRNAs targeting are poorly understood. Here we reported that miR-520a-3p was increased in mice with AS and silencing of miR-520a-3p attenuated AS process. Furthermore, inhibition of miR-520a-3p increased the expression of α-SMA and collagen. In addition, miR-520a-3p silencing inhibited the expression of M1 macrophage polarization markers and pro-inflammatory genes and promoted the M2 macrophage polarization. What’s more, forced expression of miR-520a-3p diminished IL4/IL13 induced macrophage autophagy via targeting UVRAG. Collectively, our study reveals the role of miR-520a-3p in macrophage polarization and suggests the potential of miRNA as a novel treatment target of AS.

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FPR2 Participates in Epithelial Ovarian Cancer (EOC) Progression Through RhoA Mediated M2 Macrophage Polarization: An Invitro Experimental Study

10.21203/rs.3.rs-109759/v1 ◽

2020 ◽

Author(s):

Xiaohui Xie ◽

Juan He ◽

Yaqiong Liu ◽

Weiwei Chen ◽

Kun Shi

Keyword(s):

Ovarian Cancer ◽

Western Blot ◽

Cell Lines ◽

Macrophage Polarization ◽

Ectopic Expression ◽

Ovarian Cancer Cells ◽

M2 Macrophage ◽

M2 Macrophages ◽

Invasion And Metastasis ◽

M2 Macrophage Polarization

Abstract Background: In our previous study, we found Formyl peptide receptor 2 (FPR2) promoted the invasion and metastasis of EOC and it could be a prognostic marker for EOC. In this study, we aimed to study the possible mechanism of FPR2 in promoting EOC progression.Methods: The FPR2 ectopic expression and knockdown EOC cell lines as well as their control cell lines were established and the expression change of RhoA in each cell lines was evaluated by RT-qPCR and Western-blot. Wound healing and Transwell assays were performed to detect the migrational ability of EOCs that affected by FPR2 and RhoA. The supernatant of each EOC cell lines were used to co-culture with the macrophages, and tested the M1 and M2 macrophges biomarkers by flow cytometry. THP-1 cell line was also indcued to differentiated to M1 and M2 macrophages, FPR2 and RhoA expression in each macrophage cell lines were detected by RT-qPCR and Western-blot. Results: RhoA expression was significantly increased in EOCs along with the overexpression of FPR2, which showed a positive correlation by Pearson correlation analysis. FPR2 ectopic expression would contribute to the migrational ability of EOCs, and RhoA inhibitor (C3 transferase) would impare EOCs migration. Furthermore, FPR2 stimulated the secretion of Th2 cytokines by EOCs, which induced macrophages differentiate to M2 phenotype, while RhoA inhibitor stimulate the secretion of Th1 cytokines and induce macrophages differentiate to M1 phenotype. Moreover, compared with M1 macrophages and THP-1 cells, FPR2 and RhoA expression were significantly up-regulated in M2 macrophages.Conclusion: FPR2 stimulated M2 macrophage polarization and promote invasion and metastasis of ovarian cancer cells through RhoA.

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