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

2021 ◽  
Vol 12 ◽  
Author(s):  
Kelly Gomes Santana ◽  
Renato Fraga Righetti ◽  
Cristiane Naffah de Souza Breda ◽  
Omar Alberto Domínguez-Amorocho ◽  
Theresa Ramalho ◽  
...  

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.

2021 ◽  
Author(s):  
Zhongzheng Zhi ◽  
Chenglin Zhang ◽  
Yingjie Wang ◽  
Jian Kang ◽  
Wei Yuan ◽  
...  

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.


2021 ◽  
Vol 7 ◽  
Author(s):  
Jing Rui Qi ◽  
Dian Ru Zhao ◽  
Li Zhao ◽  
Fan Luo ◽  
Mei Yang

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.


Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1303 ◽  
Author(s):  
Alexandra Pritchard ◽  
Sultan Tousif ◽  
Yong Wang ◽  
Kenneth Hough ◽  
Saad Khan ◽  
...  

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.


Author(s):  
Polytimi Paschalidi ◽  
Ioannis Gkouveris ◽  
Akrivoula Soundia ◽  
Evangelos Kalfarentzos ◽  
Emmanouil Vardas ◽  
...  

2019 ◽  
Vol 75 ◽  
pp. 105795
Author(s):  
Lu Wang ◽  
Yi Zhang ◽  
Nannan Zhang ◽  
Jingen Xia ◽  
Qingyuan Zhan ◽  
...  

2013 ◽  
Vol 71 (Suppl 3) ◽  
pp. 657.3-657
Author(s):  
V. Hernandez-Hernandez ◽  
I. Ferraz-Amaro ◽  
E. Delgado-Frías ◽  
M. Flores-Rodríguez ◽  
J. Viotti ◽  
...  

Biomaterials ◽  
2015 ◽  
Vol 37 ◽  
pp. 116-123 ◽  
Author(s):  
Daniela P. Vasconcelos ◽  
Madalena Costa ◽  
Isabel F. Amaral ◽  
Mário A. Barbosa ◽  
Artur P. Águas ◽  
...  

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