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Proinflammatory macrophage-derived microvesicles exhibit tumor tropism dependent on CCL2/CCR2 signaling axis and promote drug delivery via SNARE-mediated membrane fusion.

ABSTRACT: Background: Exosome (Exo)-based chemotherapeutic drug delivery systems have been extensively investigated; however, the therapeutic potential of other subtypes of extracellular vesicles (EVs), in particular microvesicles (MiV), seem to be overlooked. Moreover, despite a general agreement on organ tropism of EVs, few studies have clearly demonstrated that EVs specifically target tumor tissue. Methods: Proinflammatory macrophage-derived EV subpopulations comprising apoptotic bodies (ApB), MiV and Exo were isolated under differential ultracentrifugation, and further analyzed using comparative proteomic and lipid approach. Results: On the basis of EV biogenesis pathways, our data demonstrated that MiV acquire the tumor-targeting capacity probably through inheritance of CCR2-enriched cell membrane which also drives the recruitment of donor cells to tumor sites. Further, our data validate MiV utilize SNARE-mediated membrane fusion to directly discharge doxorubicin to nucleus and bypass endocytic degradation. Conclusions: Compared with other EV subtypes, MiV loaded with doxorubicin gain significant benefits in chemotherapeutic outcomes including survival rate improvements in metastatic ovarian cancer. Therefore, MiV represent a potent alterative to Exo and synthetic liposomes (Lipo) for tumor-targeting drug delivery.

SUBMITTER: Guo L

PROVIDER: S-EPMC7295053 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Proinflammatory macrophage-derived microvesicles exhibit tumor tropism dependent on CCL2/CCR2 signaling axis and promote drug delivery via SNARE-mediated membrane fusion.

Guo Ling L Zhang Ye Y Wei Runxiu R Zhang Xiaochen X Wang Cuifeng C Feng Min M

Theranostics 20200517 15

Background: Exosome (Exo)-based chemotherapeutic drug delivery systems have been extensively investigated; however, the therapeutic potential of other subtypes of extracellular vesicles (EVs), in particular microvesicles (MiV), seem to be overlooked. Moreover, despite a general agreement on organ tropism of EVs, few studies have clearly demonstrated that EVs specifically target tumor tissue. Methods: Proinflammatory macrophage-derived EV subpopulations comprising apoptotic bodies ( ...[more]

PMID: 32550891

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Project description:BackgroundChronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality worldwide, characterized by persistent respiratory symptoms and airflow limitation. The involvement of C-C motif chemokine ligand 2 (CCL2) in COPD pathogenesis, particularly in macrophage regulation and activation, is poorly understood despite its recognized role in chronic inflammation. Our study aims to elucidate the regulatory role and molecular mechanisms of CCL2 in the pathogenesis of COPD, providing new insights for therapeutic strategies.MethodsThis study focused on the CCL2-CCR2 signaling pathway, exploring its role in COPD pathogenesis using both Ccl2 knockout (KO) mice and pharmacological inhibitors. To dissect the underlying mechanisms, we employed various in vitro and in vivo methods to analyze the secretion patterns and pathogenic effects of CCL2 and its downstream molecular signaling through the CCL2-CCR2 axis.ResultsElevated Ccl2 expression was confirmed in the lungs of COPD mice and was associated with enhanced recruitment and activation of macrophages. Deletion of Ccl2 in knockout mice, as well as treatment with a Ccr2 inhibitor, resulted in protection against CS- and LPS-induced alveolar injury and airway remodeling. Mechanistically, CCL2 was predominantly secreted by bronchial epithelial cells in a process dependent on STAT1 phosphorylation and acted through the CCR2 receptor on macrophages. This interaction activated the PI3K-AKT signaling pathway, which was pivotal for macrophage activation and the secretion of inflammatory cytokines, further influencing the progression of COPD.ConclusionsThe study highlighted the crucial role of CCL2 in mediating inflammatory responses and remodeling in COPD. It enhanced our understanding of COPD's molecular mechanisms, particularly how CCL2's interaction with the CCR2 activates critical signaling pathways. Targeting the CCL2-CCR2 axis emerged as a promising strategy to alleviate COPD pathology.

Project description:Background: Age-related macular degeneration (AMD) is the most common cause of progressive and irreversible blindness in developed countries. Although the pathogenesis is not fully understood, AMD is a multifactorial pathology with an accumulation of inflammatory components and macrophages and a strong genetic predisposition. Our purpose was to investigate the association between early AMD and CCL2 (rs1024611, rs4586, rs2857656) and CCR2 (rs1799865) single nucleotide polymorphisms (SNPs) and CCL2, CCR2 serum levels in a Lithuanian population. Methods: The study included 310 patients with early AMD and 384 healthy subjects. Genotyping of CCL2 rs1024611, rs4586, rs2857656, and CCR2 rs1799865 was performed using a real-time polymerase chain reaction method, while CCL2 and CCR2 chemokines serum concentrations were analyzed using an enzyme-linked immunosorbent assay. Results: We found that the G allele at CCL2 rs1024611 was more prevalent in the early AMD group than in controls (29.2% vs. 24.1%, p = 0.032). Similarly, the C allele in CCL2 rs2857656 is more common in the early AMD group than in controls (29.2% vs. 24.2%, p = 0.037). Binomial logistic regression revealed that each G allele in rs1024611 was associated with 1.3-fold increased odds of developing early AMD under the additive model (OR = 1.322; 95% CI: 1.032–1.697, p = 0.027) as was each C allele in rs2857656 under the additive model (OR = 1.314; 95% CI: 1.025–1.684, p = 0.031). Haplotype analysis revealed that the C-A-G haplotype of CCL2 SNPs was associated with 35% decreased odds of early AMD development. Further analysis showed elevated CCL2 serum levels in the group with early AMD compared to controls (median (IQR): 1181.6 (522.6) pg/mL vs. 879.9 (494.4) pg/mL, p = 0.013); however, there were no differences between CCR2 serum levels within groups. Conclusions: We found the associations between minor alleles at CCL2 rs1024611 and rs2857656, elevated CCL2 serum levels, and early AMD development.

Dataset Information

Proinflammatory macrophage-derived microvesicles exhibit tumor tropism dependent on CCL2/CCR2 signaling axis and promote drug delivery via SNARE-mediated membrane fusion.

Publications

Proinflammatory macrophage-derived microvesicles exhibit tumor tropism dependent on CCL2/CCR2 signaling axis and promote drug delivery <i>via</i> SNARE-mediated membrane fusion.

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