The Immuno-Modulation Effect of Macrophage-Derived Extracellular Vesicles in Chronic Inflammatory Diseases

Xing, Yi; Sun, Xiaojuan; Dou, Yiming; Wang, Min; Zhao, Yanmei; Yang, Qiang; Zhao, Yanhong

doi:10.3389/fimmu.2021.785728

Cited by 19 publications

(9 citation statements)

References 198 publications

(216 reference statements)

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“…Our data demonstrated that EVs secreted from inflammatory macrophages promoted the production of catabolic factors in chondrocytes and exaggerated pathologic changes in an OA mouse model. In line with our findings, macrophage EVs have been extensively implicated in the pathology of a variety of diseases through initiating signaling pathways that impair tissue homeostasis (21). For example, EVs from inflammatory macrophages promote plaque formation in atherosclerosis via restraining the function of endothelial cells and vascular smooth muscle cells, leading to plaque progression and increased cell adhesion and thereby aggravating atherosclerosis (22,23).…”

Section: Discussionsupporting

confidence: 87%

Noncanonical Pyroptosis Triggered by Macrophage‐Derived Extracellular Vesicles in Chondrocytes Leading to Cartilage Catabolism in Osteoarthritis

Ebata

Terkawi

Kitahara

et al. 2023

Arthritis & Rheumatology

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Objective The severity of osteoarthritis (OA) and cartilage degeneration is highly correlated with the development of synovitis, which is mediated by the activity of inflammatory macrophages. A better understanding of intercellular communication between inflammatory macrophages and chondrocytes should aid in the discovery of novel therapeutic targets. We undertook this study to explore the pathologic role of inflammatory macrophage extracellular vesicles (EVs) in cartilage degeneration. Methods Macrophages were stimulated by treatment with bacterial lipopolysaccharides to mimic the state of inflammatory macrophages, and the resulting EVs were harvested for chondrocyte stimulation in vitro and for intraarticular injection in a mouse model. The stimulated chondrocytes were further subjected to RNA‐sequencing analysis and other functional assays. The action of caspase 11 was disrupted in vitro using a specific small interfering RNA or wedelolactone, and in experimental murine OA models by intraarticular injection of wedelolactone. Results Stimulated chondrocytes exhibited a significant elevation in the expression of chondrocyte catabolic factors. Consistent with these results, RNA‐sequencing analyses of stimulated chondrocytes indicated that up‐regulated genes were mainly categorized into apoptotic process and tumor necrosis factor signaling pathways, which suggests the induction of apoptotic process. Moreover, these chondrocytes exhibited a significant elevation in the expression of pyroptosis‐related molecules that were correlated with the expression of chondrocyte catabolic factors. The disruption of caspase 11 significantly alleviated pyroptotic and catabolic processes in stimulated chondrocytes and pathologic changes in collagenase‐induced and joint instability–induced OA models. Conclusion Our results provide new insight into the pathologic mechanisms of OA and suggest that noncanonical pyroptosis in chondrocytes represents an attractive therapeutic target for treatment.

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Section: Discussionsupporting

confidence: 87%

Noncanonical Pyroptosis Triggered by Macrophage‐Derived Extracellular Vesicles in Chondrocytes Leading to Cartilage Catabolism in Osteoarthritis

Ebata

Terkawi

Kitahara

et al. 2023

Arthritis & Rheumatology

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“…It has been demonstrated that M1-EVs induce proinflammatory conditions by inducing the release of proinflammatory cytokines (including TNF-α, IL-6, IL-12) and downregulating the expression of M2-TAMs (CD163) in the TME as well as stimulating apoptosis in tumor cells [ 31 , 32 ]. These are three important conditions that contribute to an overall strong anticancer effect.…”

Section: Resultsmentioning

confidence: 99%

Extracellular Vesicles from M1-Polarized Macrophages Combined with Hyaluronic Acid and a β-Blocker Potentiate Doxorubicin’s Antitumor Activity by Downregulating Tumor-Associated Macrophages in Breast Cancer

et al. 2022

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One of the main reasons for cancer’s low clinical response to chemotherapeutics is the highly immunosuppressive tumor microenvironment (TME). Tumor-ass ociated M2 macrophages (M2-TAMs) orchestrate the immunosuppression, which favors tumor progression. Extracellular vesicles (EVs) have shown great potential for targeted therapies as, depending on their biological origin, they can present different therapeutic properties, such as enhanced accumulation in the target tissue or modulation of the immune system. In the current study, EVs were isolated from M1-macrophages (M1-EVs) pre-treated with hyaluronic acid (HA) and the β-blocker carvedilol (CV). The resulting modulated-M1 EVs (MM1-EVs) were further loaded with doxorubicin (MM1-DOX) to assess their effect in a mouse model of metastatic tumor growth. The cell death and cell migration profile were evaluated in vitro in 4T1 cells. The polarization of the RAW 264.7 murine macrophage cell line was also analyzed to evaluate the effects on the TME. Tumors were investigated by qRT-PCR and immunohistochemistry. MM1-DOX reduced the primary tumor size and metastases. NF-κB was the major gene downregulated by MM1-DOX. Furthermore, MM1-DOX reduced the expression of M2-TAM (CD-163) in tumors, which resulted in increased apoptosis (FADD) as well as decreased expression of MMP-2 and TGF-β. These results suggest a direct effect in tumors and an upregulation in the TME immunomodulation, which corroborate with our in vitro data that showed increased apoptosis, modulation of macrophage polarization, and reduced cell migration after treatment with M1-EVs combined with HA and CV. Our results indicate that the M1-EVs enhanced the antitumor effects of DOX, especially if combined with HA and CV in an animal model of metastatic cancer.

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“…Besides, EVs can transport bioactive cargoes, including RNA, DNA, proteins, and lipids (Chen F et al, 2020). Indeed, it both retains many of the biological properties of their parental cells and regulates recipient cells' physiological or pathological processes (Xing et al, 2021). Of the three types of EVs, exosomes are derived from MVBs, which budding inward from a raft-like domain and, therefore, have a slightly different lipid content than the cell membrane.…”

Section: Composition and Physiological Function Of Extracellular Vesi...mentioning

confidence: 99%

Extracellular vesicles mediate biological information delivery: A double-edged sword in cardiac remodeling after myocardial infarction

et al. 2023

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Acute myocardial infarction (AMI) is a severe ischemic disease with high morbidity and mortality worldwide. Maladaptive cardiac remodeling is a series of abnormalities in cardiac structure and function that occurs following myocardial infarction (MI). The pathophysiology of this process can be separated into two distinct phases: the initial inflammatory response, and the subsequent longer-term scar revision that includes the regression of inflammation, neovascularization, and fibrotic scar formation. Extracellular vesicles are nano-sized lipid bilayer vesicles released into the extracellular environment by eukaryotic cells, containing bioinformatic transmitters which are essential mediators of intercellular communication. EVs of different cellular origins play an essential role in cardiac remodeling after myocardial infarction. In this review, we first introduce the pathophysiology of post-infarction cardiac remodeling, as well as the biogenesis, classification, delivery, and functions of EVs. Then, we explore the dual role of these small molecule transmitters delivered by EVs in post-infarction cardiac remodeling, including the double-edged sword of pro-and anti-inflammation, and pro-and anti-fibrosis, which is significant for post-infarction cardiac repair. Finally, we discuss the pharmacological and engineered targeting of EVs for promoting heart repair after MI, thus revealing the potential value of targeted modulation of EVs and its use as a drug delivery vehicle in the therapeutic process of post-infarction cardiac remodeling.

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The Immuno-Modulation Effect of Macrophage-Derived Extracellular Vesicles in Chronic Inflammatory Diseases

Cited by 19 publications

References 198 publications

Noncanonical Pyroptosis Triggered by Macrophage‐Derived Extracellular Vesicles in Chondrocytes Leading to Cartilage Catabolism in Osteoarthritis

Noncanonical Pyroptosis Triggered by Macrophage‐Derived Extracellular Vesicles in Chondrocytes Leading to Cartilage Catabolism in Osteoarthritis

Extracellular Vesicles from M1-Polarized Macrophages Combined with Hyaluronic Acid and a β-Blocker Potentiate Doxorubicin’s Antitumor Activity by Downregulating Tumor-Associated Macrophages in Breast Cancer

Extracellular vesicles mediate biological information delivery: A double-edged sword in cardiac remodeling after myocardial infarction

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