Sage Journals: Discover world-class research

Abstract

Extracellular vesicles (EVs), which are nanosized membranous structures released by diverse cell types, serve as crucial mediators of intercellular communication. Recent evidence has highlighted the dynamic transfer of various biological components, including proteins, lipids, mRNAs, non-coding RNAs, miRNAs, and DNA, via EVs. Immuno-stimulated cells actively release EVs that play a pivotal role in regulating the innate immune system. This study comprehensively reviews the current scientific findings, shedding light on the intricate biological roles of EVs in regulating innate immune cells and the overall immune system. This discussion encompasses diverse pathophysiological conditions and provides valuable insights into the multifaceted contributions of EVs to innate immune responses.

Keywords

Extracellular vesicles exosome microvesicles innate immune cells

Introduction

Extracellular vesicles (EVs) are a diverse group of lipid bilayer-enclosed secretory vesicles naturally released by various cell types.¹ This classification includes exosomes, microvesicles, and apoptotic bodies, each distinguished by a unique mechanisms of generation.¹ Figure 1(a) illustrates exosome formation initiated by the endocytosis of the plasma membrane, which leads to the creation of multivesicular bodies (MVBs) from early endosomes. Subsequent fusion of MVBs with the plasma membrane results in the release of small vesicles termed exosomes.^2,3 Microvesicles are generated through budding of the plasma membrane and typically exhibit larger dimensions than exosomes.^4,5 Apoptotic bodies, the largest of the three EV subtypes, emerge during cell apoptosis.^6,7

Figure 1.

Extracellular vesicles. (a) Generation mechanism of extracellular vesicles in mammalian cells. (b) Biological roles of extracellular vesicles in innate immune system.

Irrespective of their subtype, EVs function as carriers of various components including proteins, lipids, mRNAs, non-coding RNAs, miRNAs, and DNA, facilitating intercellular communication under diverse pathophysiological conditions.⁸ Recent studies have underscored the critical regulatory role of EVs in innate immune cells and the broader innate immune system.^9–12 Activated innate immune cells considerably contribute to the generation of EVs, initiating a cascade of immune network responses.^13–22 This work offers a comprehensive overview of the current understanding of the biological functions of EVs released by innate immune cells, shedding light on their intricate roles in intercellular communication within the context of the innate immune system.

Neutrophils and EVs

Numerous studies have provided insights into the intricate relationship between EVs and neutrophils, highlighting their pivotal roles in various physiological and pathological processes. Kuravi et al. investigated the effects of platelet-derived EVs on neutrophil adhesion to endothelial cells. Their findings revealed that platelet-derived EVs activate neutrophils and considerably enhance their interactions with endothelial cells. This suggests that platelet-derived EVs can fuel neutrophil-mediated tissue inflammation.¹³ Activated platelets have been implicated in the generation of neutrophil-derived EVs. These EVs exert regulatory effects on endothelial cell expression, specifically by influencing ICAM-1 levels and modulating neutrophil extravasation.²³ Singhto et al. extended these observations by demonstrating that EVs produced by macrophages exposed to calcium oxalate play a crucial role in stimulating interleukin-8 (IL-8) production in renal cells. In turn, this facilitates neutrophil migration and invasion, revealing a potential link between EVs and renal inflammatory processes.²⁴

Moreover, investigations into the interplay between mesenchymal stem cell (MSC)-derived EVs and neutrophil function have yielded intriguing results. Mahmoudi et al. showed that MSC-EVs considerably increased the survival of neutrophils in patients with severe congenital neutropenia, positioning MSC-EVs as a promising therapeutic candidate for combating serious infections associated with congenital neutropenia.¹⁴ However, contrasting findings indicated that MSC-EVs reduced the number of neutrophils in patients with chronic granulomatous disease. Nevertheless, these EVs upregulate the inflammatory activity of neutrophils, thereby underlining the complex and context-dependent effects of MSC-EVs on neutrophil function.²⁵ Wang et al. explored the role of MSC-EVs in polymorphonuclear leukocyte (PMN)-associated neuronal ischemia. Their investigations revealed that MSC-EVs play a crucial role in reducing the infiltration of leukocytes, including PMNs, into the brain. This suggests a potential therapeutic avenue for utilizing MSC-EVs to prevent PMN-associated neuronal ischemia.²⁶

Leal et al.²⁷ investigated the relationship between tumor-derived EVs and neutrophil extracellular trap (NET) formation. Their study demonstrated that tumor-derived EVs actively contribute to the formation of NETs in mice exposed to granulocyte colony-stimulating factor, suggesting a collaborative role between tumor-derived EVs and neutrophils in the development of cancer-associated thrombosis.

Additionally, EVs produced by the stimulated neutrophils demonstrated functional activity. Vargas et al. investigated the effect of neutrophil-derived EVs on the proliferation of airway smooth muscles (ASM) in patients with asthma. Their results indicated that EVs actively generated by lipopolysaccharide (LPS)-stimulated neutrophils play a role in promoting ASM proliferation. This sheds light on the potential involvement of neutrophil-derived EVs in the airway remodeling observed in patients with asthma.²⁸

The immunomodulatory role of neutrophils is contingent on the composition of the released EVs, thereby dictating whether they exert suppressive or promotional effects on innate immune responses. For instance, Zhu et al. highlighted that EVs released from PMNs upon stimulation by the pro-inflammatory cytokine TNF-α enhance the activation of M1 macrophages.²⁹ Furthermore, Jiao et al. demonstrated that miR-30d-5p-enriched EVs from neutrophils contribute to sepsis-related acute lung injury by inducing M1 macrophage polarization.³⁰

In contrast, neutrophil-derived EVs have demonstrated substantial anti-inflammatory effects.^31,32 Zhang et al. reported that EVs originating from neutrophils elicit tumor cell apoptosis by delivering cytotoxic proteins and activating the caspase signaling pathway.³³

Collectively, these studies underscore the multifaceted interactions between EVs and neutrophils and provide valuable insights into their roles in inflammation, immune responses, and disease pathogenesis. Further exploration of these intricate relationships holds promise for the development of novel therapeutic strategies targeting EV-mediated regulation of neutrophil function in various clinical contexts.

Natural killer cells and EVs

The intricate interplay between natural killer (NK) cells and EVs reveals a complex landscape of immune modulation and functional crosstalk. Several studies have suggested that NK cell-derived EVs exert cytotoxic effects on target cells and modulate immune response.^34–39 For example, Lugini et al. highlighted the dynamic nature of NK cell-derived EVs by demonstrating that activated NK cells release EVs expressing killer proteins, such as Fas ligands and perforin molecules, along with typical protein markers of NK cells. This suggests a crucial role for NK cell-derived EVs in immune surveillance and homeostasis.¹⁶ Moreover, EVs from activated NK cells induce apoptosis in target cells by delivering cytotoxic proteins including perforin, granzyme A, granzyme B, and granulysin.³⁵ NK cell-derived EVs constitute a vital component of immune cell functionality and facilitate immune responses. These EVs have been shown to transport an array of cytotoxic proteins and nucleic acids originating from NK cells, thus exhibiting therapeutic potential for treating diseases.⁴⁰

In addition, Sokolov et al. reported that EVs derived from NK cells influence trophoblast cells by promoting their migration while simultaneously inhibiting their proliferation through the phosphorylation of STAT3 at Ser727.⁴¹ Moreover, EVs from IL-1β-stimulated NK cells impact endothelial cells by reducing proliferation, migration, activating caspases, and altering marker expression.³⁴

Furthermore, NK cell-derived EVs not only carry cytotoxic proteins and cytokines but also contain miRNAs. In a novel perspective, NK cell-derived EVs were found to alleviate depression-like symptoms by carrying miR-207, which targets and regulates the function of astrocytes, offering a potential avenue for exploring the interplay between the immune system and mental health.⁴² Wang et al. demonstrated that EVs with miR-1249-3p cargo derived from NK cells could reduce inflammation and insulin resistance via the SKOR1 signaling pathway in a mouse model.⁴³

Additionally, NK cell-derived miRNAs-enriched EVs (miR-10b-5p, miR-92a-3p, and miR-155-5p) promote the downregulation of Th1 cell IFN-γ and IL-2 production.⁴⁴ NK cell-derived EVs alleviate TGF-β-dependent immune suppression.⁴⁵ Additionally, EVs derived from NK cells inhibit tumor growth and counteract the TGF-β-dependent immune escape mechanism.⁴⁷

Numerous studies have underscored that EVs derived from NK cells encapsulating miRNAs manifest anti-tumor efficacy by inhibiting cancer cell proliferation.^46,47 Additionally, Neviani et al. has demonstrated that EVs released from NK cells can inhibit the immune escape of cancer cells.⁴⁸ EVs derived from NK cells, particularly EVs containing IL-15 and IL-21 released upon NK cell stimulation, have been observed to augment cytotoxic activity.⁴⁹ Similarly, in a study conducted by Kim et al. IL−15/21- bearing EVs derived from NK cells were found to enhance crucial cytotoxic molecule activation in the apoptotic pathway, thereby improving anti-tumor effects in hepatocellular carcinoma cells.⁵⁰

While EVs released by normal cells play essential roles in intercellular communication, tumor cell-derived EVs exhibit immunosuppressive properties, shaping the tumor microenvironment and influencing peripheral tolerance in cancer patients.⁵¹ Liu et al. uncovered a pivotal role for tumor cell-derived EVs in promoting tumor growth by inhibiting the IL-2-mediated activation of NK cells.⁵² Furthermore, Huyan et al. illustrated that EVs harboring miR-221-5p and miR-186-5p released from cancer cells inhibited NK cell function by impeding the stability of mRNAs associated with DAP10, CD96, and perforin genes.⁵³ The diverse functions of EVs were underscored by Shoae-Hassani et al. in their investigation of neuroblastoma-and NK cell-derived EVs. Their findings indicated that neuroblastoma-derived EVs act as tumor promoters by creating a supportive niche for tumor growth. In contrast, naïve NK cells exposed to EVs from NK cells previously co-cultured with neuroblastoma cells displayed considerably enhanced cytotoxicity against neuroblastoma cells.⁵⁴ Further insights into the immunotherapeutic landscape revealed that EV-circUHRF1, which is predominantly secreted by hepatocellular carcinoma (HCC) cells, contributes to immunosuppression by inducing NK cell dysfunction, potentially conferring resistance to anti-PD1 immunotherapy in HCC patients.⁵⁵

The multifaceted involvement of NK cell-derived EVs in diverse physiological processes underscores their potential as therapeutic targets and highlights the need for further exploration to unravel the intricate mechanisms governing their functions.

Dendritic cells and EVs: orchestrating immune responses

Dendritic cells (DCs), recognized as pivotal antigen-presenting cells, are subject to intricate modulation by EVs, unveiling a realm of immune regulatory functions. In a noteworthy study, EVs derived from mast cells were found to activate immature DCs, inducing the upregulation of Major Histocompatibility Complex (MHC) class II, CD80, CD86, and CD40. This cascade of events not only highlights the stimulatory role of EVs in DCs activation but also emphasizes their involvement in the initiation of adaptive immunity orchestrated by DCs.¹⁷

Tumor derived EVs originating from tumor cells are implicated in the suppression and evasion of immune responses.⁵⁶ Expanding on this theme, a separate investigation revealed that EVs derived from TS/A tumor cells exerted control over DCs maturation. These tumor-derived EVs induced the accumulation of myeloid precursors in the spleen by targeting CD11b, concurrently suppressing the differentiation of myeloid precursors into DCs. This dual impact suggests a nuanced regulatory role of tumor-derived EVs in the intricate process of DCs maturation.⁵⁷

In addition, Salimu et al. demonstrated that prostate cancer-derived EVs can suppress the function of DCs by attenuating the induction of CD73 on DCs through the action of EVs containing prostaglandin E2.⁵⁸ Likewise, Gassmann et al. emphasized that EVs released by Ewing sarcoma may induce both local and systemic pro-inflammatory conditions, by inhibiting CD4⁺ and CD8⁺ T cell proliferation and suppressing IFN-γ release, while simultaneously promoting the secretion of IL-10 and IL-6. Furthermore, these EVs contribute to the suppression of adaptive immunity by impairing the differentiation and function of antigen-presenting cells, such as DCs.⁵⁹

Dengue virus (DENV), which is disseminated through Aedes spp. mosquitoes, is one of the most important arboviral infections globally.⁶⁰ Martins et al. highlighted that DENV can alter the composition of EVs released from primary DCs, favoring conditions conducive to viral propagation.⁶¹ Izquierdo-Serrano et al. demonstrated that EVs derived from Listeria monocytogenes infected DCs elicited an anti-pathogenic state, thereby enhancing responsiveness to subsequent bacterial infections with L. monocytogenes in immature recipient DCs.⁶² Interestingly, both in vitro and in vivo studies have revealed that Porphyromonas gingivalis, a prominent oral pathogen, induces DCs senescence. This effect was mediated by paracrine actions facilitated by EVs derived from DCs co-cultured with P. gingivalis.^63,64 Moreover, an in vivo study demonstrated that EVs released from macrophages infected with Mycobacterium bovis and M. tuberculosis (BCG) induced the activation and maturation of DCs derived from mouse bone marrow.⁶⁵

Additionally, EVs derived from mesenchymal stromal cells influence DCs function, thereby affecting immune responses. Reis et al. demonstrated that miR-21-5p enriched in EVs released from mesenchymal stromal cells modulates DCs function and migration. Their study revealed that transfection of DCs with miR-21-5p mimics considerably reduced DCs migration toward the CCR7 ligand CCL21, along with a tendency toward decreased CCR7 protein expression and reduced production of pro-inflammatory cytokines.⁶⁶

DCs contribute to immune regulation not only through direct antigen presentation but also by releasing EVs that carry immune-modulating molecules. These EVs have been shown to express biologically functional MHC and T-cell co-stimulatory molecules, enabling them to directly activate adaptive immune responses.⁶⁷ Building on this concept, Gao et al. demonstrated that DCs-derived EVs containing TNF-α play a critical role in activating the endothelial NF-κB signaling pathway, which contributes to vascular inflammation and the progression of atherosclerosis.¹⁸ Furthermore, these EVs have been found to express functional IL-15 receptor alpha, which promotes NK cell proliferation and enhances IFN-γ secretion.⁶⁸

In addition to their role in immune activation, DC-derived EVs have gained attention for their potential to counteract tumor immune evasion. Studies have shown that these EVs can induce caspase-dependent apoptosis in tumor cells and enhance NK cell responses, thereby strengthening anti-tumor immunity.^69–74

In summary, DC-derived EVs are indispensable immune regulators that play a dual role in modulating adaptive immunity and influencing the intricate balance of immune responses in health and disease. Further exploration of these interactions holds promise for the identification of novel therapeutic targets and strategies for the treatment of immune-related disorders.

Macrophages and EVs: orchestrating inflammatory responses

Compelling evidence continues to reveal the pivotal role of EVs as indispensable regulators of macrophage-mediated inflammatory responses. Lee et al. demonstrated dynamic alterations in EVs containing miRNA repertoires throughout the progression of acute lung injury, underscoring the intricate interplay between EVs and pulmonary inflammation.^4,75 Furthermore, their findings emphasized the effective modulation of alveolar macrophage phenotypes by EV-miRNAs, reinforcing the crucial role of pulmonary EVs in shaping the trajectory of lung inflammation.^75–77

The involvement of macrophage-derived EVs in diverse immunopathological processes has been extensively explored. These EVs are predominant in bronchoalveolar lavage fluid during infection-induced acute lung injury.¹⁹ Ye et al. provided insights into the pro-inflammatory nature of macrophage-derived EVs, demonstrating their role as major contributors to neutrophil recruitment and activation.²⁰ Additionally, Jiao et al. uncovered the impact of EVs produced by macrophages under hemorrhagic shock, highlighting their ability to induce reactive oxygen species (ROS) production within polymorphonuclear leukocytes (PMNs) and subsequent PMN necroptosis.⁷⁸ Moreover, EVs derived from LPS-induced inflammatory macrophages impair ion channel proteins in pulmonary epithelial cells, thereby promoting epithelial cell dysfunction and damage.⁷⁹

Remarkably, the biological activities of macrophage-derived EVs appear to depend on the polarization status of macrophages. An in vivo study highlighted that EVs released from M1 macrophages have been documented to serve as carriers for the chemotherapeutic agent paclitaxel, facilitating its targeted delivery to tumor tissues and resulting in an augmentation of therapeutic efficacy in tumor chemotherapy.⁸⁰ Additionally, M1 macrophages suppress trophoblast migration and invasion in vitro by releasing EVs containing miRNAs.⁸¹ Interestingly, Jing et al. pointed out that EVs derived from trophoblasts could be transferred into macrophages to induce M1 polarization through the IκBα-mediated NF-κB pathway. Furthermore, M1 macrophages induced by EVs from trophoblasts were found to suppress the proliferation, migration, and apoptosis of trophoblasts via TNF-α.⁸²

Wang et al. showed that circUbe3a in M2 macrophage-derived small EVs promotes cardiac fibroblast proliferation, migration, and phenotypic transformation by sponging miR-138 5p and translationally repressing RhoC. Their study demonstrated the potential of EVs and circUbe3a to exacerbate myocardial fibrosis following myocardial infarction.⁸³ Furthermore, another study revealed that miR-378a-3p contained in EVs derived from M2 macrophage- reduces cardiomyocyte pyroptosis by inhibiting human antigen receptor expression and translocation to the cytoplasm, leading to the destabilization of NLRP3 and blocking the activation of the NLRP3/Caspase-1/GSDMD pathways after myocardial infarction.⁸⁴

Moreover, Wang et al. revealed that bone fracture healing in individuals with diabetes is considerably delayed due to an imbalance in the osteoimmune microenvironment, which is characterized by an abnormal increase in M1 macrophages and a decrease in M2 macrophages. Additionally, they found that M2-EVs have the potential to promote the transformation of macrophages from M1 to M2 by targeting the PI3 K/AKT pathway. This suggests a promising therapeutic approach for improving the diabetic osteoimmune microenvironment and provides a new perspective and potential treatment strategy for delayed bone repair in individuals with diabetes.⁸⁵

In addition, Gao et al. assessed the activity of EVs derived from RBC in a sepsis model and found that EVs exacerbated the inflammatory response in both serum and lung tissue by increasing the production of pro-inflammatory factors such as TNF-α, IL-6, and IL-1β.⁸⁶ This leads to the reduced survival of mice with sepsis. Furthermore, transfusion of macrophages pretreated with red blood cell-derived EVs into mice worsened systemic inflammation. In vitro experiments have confirmed the pro-inflammatory properties of EVs, as they elevate cytokine levels in lipopolysaccharide-stimulated macrophages and promoted macrophage polarization to a pro-inflammatory phenotype. RBC-derived EVs play a significant role in promoting macrophage polarization to a pro-inflammatory phenotype during sepsis. The study demonstrates that these EVs enhance macrophage cytokine production by activating the TLR4-MyD88-NF-κB-MAPK signaling pathway, which ultimately aggravates the inflammatory response. These findings suggest that the inflammatory effects of RBC-derived EVs are critical for understanding transfusion-related immunomodulation, and offer potential therapeutic avenues for patients undergoing blood transfusions, particularly in the context of inflammation and sepsis.⁸⁶

In addition, EVs derived from the human umbilical cord (hUC-EVs) and arsenic trioxide have been shown to be effective in treating acute graft-versus-host diseases through immunomodulation. The study revealed that hUC-EVs loaded with arsenic trioxide promote the transition of M1 to M2 type macrophages via the mTOR autophagy pathway.⁸⁷

This dichotomy in macrophage polarization extends to the effects of EVs on cancer cell behavior. Studies have revealed that EVs derived from M2 macrophages considerably promote cancer cell migration and invasion both in vitro and in vivo.^88–91 Guan et al. revealed that exosomes derived from M2 macrophages accelerate the migration and invasion of lung adenocarcinoma (LUAD) cells. Specifically, miR-1911-5p contained within EVs secreted by M2 macrophages enhances LUAD cell migration and invasion by targeting the CELF2 protein, leading to the downregulation of ZBTB4. The inhibition of ZBTB4 promotes LUAD progression.⁹¹ In addition to their role in cancer progression, macrophage-derived EVs have also been shown to modulate inflammation and pain signaling by transferring functional proteins and RNAs to recipient cells, suggesting their broader relevance in inflammatory conditions.⁹²

Conversely, EVs derived from tumors play a pivotal role in orchestrating the polarization of macrophages within the tumor microenvironment, thereby promoting an immunosuppressive environment favorable to tumor progression.^93–95 For instance, tumor-derived EVs enriched with miR-19b-3p have been shown to facilitate M2 macrophage polarization in lung adenocarcinoma, which in turn promotes tumor metastasis by enhancing the secretion of oncogenic EVs carrying LINC00273 and activating the Hippo signaling pathway.⁹⁵ Additionally, tumor-derived EVs can influence macrophage metabolic programming and cytokine secretion profiles, further supporting tumor growth and immune evasion.^93,94

Numerous studies have revealed that EVs derived from stem cells can regulate the function and proliferation of macrophages in various diseases.^96–100 For instance, Li et al. suggested that human umbilical cord mesenchymal stem cell-derived EVs have potential as a therapeutic approach for osteoarthritis by promoting M2 macrophage polarization, anti-inflammatory cytokine expression, and modulating the PI3K-Akt signaling pathway.⁹⁷

Furthermore, it has been elucidated that mesenchymal stromal cells possess the capacity to regulate macrophages. Hwang et al. emphasized that mesenchymal stromal cells induce anti-inflammatory effects by promoting the differentiation and maturation of M2 macrophages.¹⁰¹

Additionally, bacteria-derived EVs can induce macrophage polarization and modulate macrophage function. Bhatnagar et al. demonstrated that macrophages infected with M. avium stimulate uninfected macrophages through EV production, showing diverse inflammatory responses orchestrated by biologically active M1 macrophage-derived EVs in infectious diseases.¹⁰² Kim et al. demonstrated that EVs derived from Lactobacillus plantarum facilitate anti-inflammatory M2 macrophage polarization. Furthermore, their findings underscored the therapeutic potential of EVs released from L. plantarum in mitigating inflammation-associated responses linked to M1 macrophage activation.¹⁰³

In summary, the intricate interplay between macrophages and EVs has emerged as a central player in the orchestration of inflammatory responses. The diverse functions of macrophage-derived EVs, which are influenced by their polarization status, offer new avenues for understanding and potentially manipulating immune and inflammatory processes in health and disease. Further exploration of these interactions holds promise for the advancement of diagnostic and therapeutic strategies against inflammatory diseases.

Antigen presenting cells and EVs: bridging innate and adaptive immunity

EVs released by antigen-presenting cells (APCs), such as DCs and macrophages, carry surface MHC class I and class II molecules and therefore can potentially stimulate CD8 and CD4 T cells, respectively,.^104,105 However, the ability of peptide-MHC (pMHC) -containing EVs derived from APCs to activate T cells depends on their concentration and the presence of co-stimulatory molecules on the EV surface.¹⁰⁶ Furthermore, the quality of specific immune cell activation is influenced by the antigen presentation mechanisms employed. EVs contribute to antigen presentation via three main mechanisms.^9,107,108 First, in direct antigen presentation, EVs derived from professional APCs display MHC-peptide complexes, along with co-stimulatory and adhesion molecules, directly engaging with T cells to activate an immune response (Figure 2(a)).^109,110 Second, in semi-direct antigen presentation (also known as the cross-dressing process), EVs bind to the surface of DCs. These EVs remain on the DCs membrane, allowing their pMHC complexes to be directly presented to T cells, while co-stimulatory signals are provided by DCs.¹⁰⁹ This process enhances immune synapse formation by increasing the density of pMHC complexes, thereby facilitating more efficient T cell activation (Figure 2(b)).^111,112 Finally, in indirect antigen presentation (cross-presentation), EVs transfer their antigenic peptides to MHC molecules of recipient APCs. The recipient APCs load these peptides onto their own MHC molecules and present them to T cells, initiating a specific immune response (Figure 2(c)).¹¹³ Studies have highlighted the significant potential of EVs in vaccination and tumor immunity, emphasizing their critical role in cross-presentation, which is essential for immune responses against tumors and infections. In tumor immunity, migratory DCs release EVs that transfer antigens to lymph node-resident DCs, thereby enhancing antigen presentation. As a result, EVs carrying pMHC-I complexes from these resident DCs primed and activated the naïve CD8+ T cells. These findings underscore the potential of EVs in immunotherapy, opening new avenues for cancer and viral treatments through targeted antigen delivery.^114,115

Figure 2.

Mechanisms of antigen presentation by EVs. (a) Direct presentation: EVs display pre-loaded MHC-peptide complexes to directly activate T cells. (b) Semi-direct presentation: EVs bind to the surface of DCs and provide co-stimulatory signals when DCs present their MHC-peptide complexes. (c) Indirect presentation: EVs transfer their antigenic peptides to the MHC molecules of recipient APCs, recipient APCs present these complexes to T cells.

Mast cells and EVs: unraveling the intricacies of immune regulation

Although the biological relationship between mast cells and EVs remains a mystery, the current research sheds light on this enigmatic topic, unraveling the intricate interplay between these two entities. In a noteworthy study, mast cell-derived EVs emerged as potent modulators of immune responses. These EVs were found to promote the mitogenic activity of T and B lymphocytes both in vitro and in vivo, revealing their crucial role in the immune regulatory system.²¹ Mast cell-derived EVs exhibit the capacity to evoke diverse immune responses from various immune cell types. Specifically, Vukman et al. highlighted that EVs derived from mast cell induce TNF-α expression from other mast cells.¹¹⁶ Remarkably, a recent study revealed compelling insights into the potential exacerbation of eosinophilic allergic inflammation. This exacerbation appears to be linked to the activation of human group 2 innate lymphoid cells induced by miR103a-3p derived from mast cells. These findings suggest that the activation of human group 2 innate lymphoid cells by mast cell derived miR103a-3p may play a pivotal role in intensifying eosinophilic allergic inflammation.¹¹⁷

Moreover, Zou et al. have underscored that EVs originating from mast cells play a pivotal role in exacerbating oxidative stress and eliciting inflammatory responses in asthmatic mice, a phenomenon mediated by the DDAH1/Wnt/β-catenin signaling axis. In the present study, elevated expression of miR-21 in asthmatic mice was correlated with reduced levels of antioxidant enzymes and an increase in inflammatory cell counts, effects that were successfully mitigated upon inhibition of miR-21.¹¹⁸ This study elucidated that miR-21 specifically targets DDAH1, orchestrating the modulation of the Wnt/β-catenin signaling pathway. Concurrent downregulation of DDAH1 compromised the efficacy of the miR-21 inhibitor. Consequently, the researchers posit that miR-21, released from mast cell-derived EVs, instigates oxidative stress and inflammation in asthmatic mice through the intricate orchestration of the DDAH1/Wnt/β-catenin signaling axis.¹¹⁸

Expanding the spectrum of mast cell-derived EV functions, another study revealed their ability to upregulate the expression of plasminogen activator inhibitor type-1 in endothelial cells. This finding suggests a potential role of mast cell-derived EVs in procoagulant states associated with endothelial dysfunction syndromes.²²

To explore the multifaceted roles of mast cell-derived EVs, researchers have investigated their impact on airway epithelial cells and the epithelial to mesenchymal transition (EMT).¹¹⁹ Yin et al. conducted an in-depth investigation into the influence of EVs on the transition from an epithelial to a mesenchymal state. This in vitro study systematically explored the effects of mast cell-derived EVs on epithelial A549 cells by employing analyses at the RNA and protein levels along with phosphorylation events using a phosphorylated protein microarray.¹¹⁹ The results of this investigation shed light on the intricate communication between mast cells and airway epithelial cells, particularly in the context of EMT, and provide valuable insights into the mechanisms involved in airway remodeling. These findings have implications for respiratory conditions such as asthma and chronic obstructive pulmonary disease.

Furthermore, emphasizing the multifaceted roles of mast cell-derived EVs, another study demonstrated their capacity to stimulate the antigen-presenting ability of immature DCs. This stimulation was evidenced by the upregulation of MHC class II, CD80, CD86, and CD40 expression. Additionally, this study highlighted the efficient uptake of EV-containing antigens by DCs, shedding light on the indispensable role of mast cell-derived EVs in facilitating collaborative interactions between mast cells and DCs within the innate immune system.¹⁷

A recent study revealed that EVs from tonsil-derived mesenchymal stem cells (T-MSCs) possess the ability to modulate gene expression in mast cells. Notably, stimulation of Toll-like receptors (TLRs) induces alterations in both the size and quantity of released EVs particles. Intriguingly, EVs from T-MSCs primed with TLRs induced a reduced number of transcriptomic changes in mast cells compared with unprimed EVs. This phenomenon influences a more discerning spectrum of genes, highlighting the specificity of the impact of TLR-primed T-MSC EVs on mast cell gene expression.¹²⁰

Numerous studies have shown that EVs originating from cancer cells elicit mast cell activation.^121–123 In a study by Shefler et al. EVs derived from non-small-cell lung cancer promoted lung angiogenesis.¹²² These EVs potentially activate mast cells within the lung tumor microenvironment, leading to the release of various cytokines and chemokines. The cumulative effect of this interplay suggests a mechanism by which non-small cell lung cancer-derived EVs promote angiogenesis in the lungs.¹²²

Additionally, the reciprocal interaction between mast cells and cell membranes of lung tumor cells induces mast cell activation, resulting in the release of miRNAs encapsulated within EVs. This intricate intercellular communication underscores the dynamic involvement of mast cells in the tumor microenvironment. The miRNAs released within EVs may play a role in modulating signaling pathways, contributing to the complex regulatory processes associated with mast cell-tumor cell interactions in the context of lung tumors.¹²⁴

In summary, emerging evidence suggests that mast cell-derived EVs play a pivotal role in modulating immune responses, influencing immune cell activity, and contributing to an intricate network of interactions within the immune system. Further exploration of the biological intricacies of mast cell-EV interactions holds promise for uncovering novel insights into immune regulation and potential therapeutic avenues for immune-related disorders.

Conclusions: unveiling the potential of EVs in innate immunity

This review highlights the pivotal role of EVs as key regulators of innate immunity, emphasizing their capacity to mediate intercellular communication and modulate immune responses. The dynamic release of EVs by innate immune cells in response to external stimuli underscores their intricate involvement in immune system regulation, as illustrated in Figure 1(b) and detailed in Tables 1 and 2. Furthermore, the identification of critical EV-associated components relevant to innate immune disorders positions these vesicles as promising candidates for diagnostic and therapeutic applications in a range of immune-related conditions.

Table 1.

Biological functions of extracellular vesicles (EVs) derived from innate immune cells.

EV source	Target cell	Function	Ref
Neutrophil EVs	ASMs	Promotion the proliferation of ASM	²⁸
Neutrophil EVs	Macrophages	Regulation of macrophage polarization	^29,30
Neutrophil EVs	Tumor cells	Promotion of tumor cell apoptosis	³³
NK cell EVs	Lung M1 Macrophages	Improvement of PA-induced lung injury through promoting M1 lung macrophage polarization	¹²⁵
NK cell EVs	Astrocytes	Reduction of pro-inflammatory cytokine levels (IL-1β, IL-6, and TNF-α)	⁴²
NK cell EVs	Neuroblastoma	Induction of efficient and greater cytotoxicity against NB tumors	⁵⁴
NK cell EVs	NK cells	Enhancement of NK cell cytotoxic activity	⁴⁹
NK cell EVs	trophoblast cells	Effect on trophoblast cell functionality	⁴¹
NK cell EVs	endothelial cells	Regulation of endothelial cell proliferation and migration	³⁴
NK cell EVs	PBMCs	Induction of HLA-DR and co-stimulatory molecule expression on monocytes and CD25 expression on T cells	³⁹
NK cell EVs	Th cells	Downregulation of Th1 cell function	⁴⁴
NK cell EVs	Cancer cells	Inhibition of cancer cell immune escape	⁴⁸
NK cell EVs	Cancer cells	Inhibition of cancer cell proliferation	^46,47
NK cell EVs	Tumor	Anti-tumor effect	⁵⁰
Mast cell EVs	DCs	Activation of immature DCs with upregulation of MHC class II, CD80, CD86, and CD40, leading to increased antigen-presenting capacity	¹⁷
DCs EVs	NK Cells	Activation of NK cells via TNF superfamily ligands Activation of NK cells through TNF superfamily ligands, leading to IFN-γ release via TNF signaling and caspase pathways, ultimately promoting tumor cell death	¹⁵
Infected DCs EVs	DCs	Regulation of DCs function	^62–65
DCs EVs	NK cells	Facilitation of NK cell proliferation	⁶⁸
DCs EVs	T cells	Expression of biologically functional MHC and T-cell co-stimulatory molecules	⁶⁷
DCs EVs	Endothelial cells	Expression of TNFα activate the endothelial NK-kB signaling pathway, trigger vascular inflammation and atherosclerosis	¹⁸
Macrophage EVs	Neutrophils	Induction of neutrophil recruitment and activation	²⁰
Macrophage EVs	PMNs	Significant induction of ROS production in PMNs, leading to necroptosis	⁷⁸
Macrophage EVs	Epithelial cells	Promotion of epithelial cell failure	⁷⁹
M1 macrophage EVs	Tumor cells	Anti-tumor effects	⁸⁰
M1 macrophage EVs	Trophoblast	Suppression of trophoblast cell migration	⁸¹
M1 macrophage EVs	Trophoblast	Regulation of trophoblast function	⁸²
M2 macrophage EVs	Fibroblast	Induction of functional changes in cardiac fibroblasts	⁸³
M2 macrophage EVs	Cardiomyocytes	Reduction of cardiomyocyte proptosis	⁸⁴
M2 macrophage EVs	Gastric cancer cells	Mediation of intercellular transfer of ApoE, activating the PI3K-Akt signaling pathway in recipient gastric cancer cells to remodel the cytoskeleton and support migration	⁸⁸
M2 macrophage EVs	Colon cancer cells	Induction of colorectal cancer cell migration and invasion	⁸⁹
Mast cell EVs	Mast cells	Induction of TNF-α expression in mast cells	¹¹⁶
Mast cell EVs	Human group 2 innate lymphoid cells	Activation of human group 2 innate lymphoid cells	¹¹⁷
Mast cell EVs	Lung cells	Promotion of oxidative stress and inflammation	¹¹⁸
Mast cell EVs	Airway epithelial cell	Alteration of epithelial cell morphology and gene expression	¹¹⁹
Mast cell EVs	Tumor cells	Modulation of recipient cell signaling events through receptor-ligand interactions	¹²⁶
Mast cell EVs	Endothelial cells	Induction of plasminogen activator inhibitor type 1 (PAI-1) expression in endothelial cells, detectable at the level of PAI-1 mRNA protein synthesis	²²
Mast cell EVs	DCs	Induction of immature DCs to up-regulate MHC class II, CD80, CD86, and CD40 molecules	¹⁷

Table 2.

Biological functions of extracellular vesicles (EVs) from other cell types on the innate immune cells.

EV source	Target cell	Function	Ref
Platelet EVs	Neutrophils	Promotion of the interaction between neutrophils and endothelial cells	¹³
Platelet EVs	Neutrophils	Induction of neutrophil-derived EV generation	²³
Calcium oxalate-exposed Macrophages EVs	Neutrophils	Stimulation of IL-8 production from renal cells and induction of neutrophil migration and invasion	²⁴
HS-activated AM EV	Neutrophils	Production of ROS and induction of PMN cell death	⁷⁸
MSC EVs	Neutrophils	Increase in neutrophil survival in severe congenital neutropenia patients	¹⁴
MSC EVs	Neutrophils	Reduction in neutrophil count in chronic granulomatous disease patients	²⁵
MSC EVs	PMNs	Decrease in brain infiltration of leukocytes, including PMNs	²⁶
Tumor EVs	Neutrophils	Formation of NET in mice that are exposed to the granulocyte colony-stimulating factor Formation of neutrophil extracellular traps in mice exposed to granulocyte colony-stimulating factor	²⁷
Tumor EVs	NK cells	Decline of cytotoxic activity, thereby promoting tumor progression	⁵¹
Tumor EVs	NK cells	Growth of tumors by blocking IL-2-mediated activation Enhancement of tumor growth by blocking IL-2-mediated activation	⁵²
Cancer cell EVs	NK cells	Induction of immunosuppression by impairing NK cell function	⁵⁵
Cancer cell EVs	NK cells	Modulation of NK cell function	⁵³
Infected RBCs	NK cells	Promotion of NK cell activation	¹²⁷
Bacterial EVs	NK cells	Induction of NK cell anti-tumor cytokine production	¹²⁸
Viral EVs	NK cells	Suppression of NK cell function	^129,130
TS/A tumor cell EVs	DCs	Induction of myeloid precursor accumulation in the spleen via targeting CD11b, and regulation of their maturation	⁵⁷
Tumor EVs	DCs	Suppression of DCs maturation and antigen presentation	⁵⁸
Ewing Sarcoma EVs	DCs	Disruption of APC differentiation and adaptive immunity	⁵⁹
Mesenchymal stromal cell EVs	DCs	Modulation of DCs function	⁶⁶
Epithelial EVs	Macrophage	Activation of tissue macrophages via MV-containing Cav-1/hnRNPA2B1 complex-bound miR-17/93	⁵
Alveolar epithelial Type-I cells EVs	Alveolar Macrophage	Promotion of inflammasome activation, neutrophil recruitment, and M1 macrophage polarization in response to P. aeruginosa pneumonia	⁷⁵
Epithelial EVs	Macrophage	Promotion of macrophage-driven lung inflammatory responses	⁷⁷
BALF EVs	Macrophage	Promotion of macrophage recruitment and differential regulation of AMs cytokine production, inflammatory mediator release, and TLR expression	¹⁹
Lactobacillus plantarum EVs	Macrophages	Induction of monocytic cell differentiation into macrophages	¹⁰³
RBC EVs	Macrophages	Regulation of inflammatory responses	⁸⁶
hUC EVs	Macrophages	Promotion of M1 to M2 Macrophage Transition	⁸⁷
Tumor EVs	Macrophages	Regulation of macrophage polarization	^93–95
Mesenchymal stromal cell EVs	Macrophages	Promotion of M2 macrophage differentiation and mutation	¹⁰¹
Aspergillus fumigatus EVs	Macrophages, BMDN	Induction of TNF-α and CCL2 production in bone marrow-derived neutrophils, with enhancement of TNF-α and IL-1β production in response to conidia	¹³¹
Mesenchymal stem cell EVs	Mast cells	Modulation of gene expression in mast cells	¹²⁰
Tumor cell EVs	Mast cells	Promotion of mast cell activation in the tumor microenvironment	¹²²

Despite their great potential, EVs face several significant challenges that must be addressed to fully realize their clinical applications. These challenges include developing high-efficiency methods for isolating EVs, improving the delivery of therapeutic cargo, ensuring the stability of EVs in the bloodstream, accurately targeting specific tissues, and achieving effective delivery of therapeutic cargo inside cells. Overcoming these obstacles is crucial for harnessing the full therapeutic potential of EVs and expanding their use in disease prevention, diagnosis, and treatment. Continued research is essential to resolve these issues and unlock new opportunities for developing innovative therapies across a wide range of diseases.

In conclusion, this review provides a comprehensive synthesis of existing knowledge on the biological functions of EVs within the innate immune system, offering a robust foundation for future investigations. By addressing existing knowledge gaps and exploring innovative strategies, this review aspires to catalyze advancements in the field. Continued research into EV-based diagnostics and therapeutics holds great promise for transforming our understanding of innate immunity and fostering the development of novel clinical interventions.

Footnotes

Acknowledgement

During the preparation of this work, the authors used ChatGPT to enhance language and readability. Following its use, the content was thoroughly reviewed and edited with input from native speakers. The authors take full responsibility for the final version of the manuscript.

ORCID iDs

Budjav Jadamba

Jihye Park

Heedoo Lee

Author contributions

B.J. and H.L. developed the outline of the study; B.J., J.P. prepared the original draft; and H.L. reviewed and edited the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Global LAMP Program of the National Research Foundation of Korea (NRF), grant (No. RS2024-00444460), and the Korea Basic Science Institute (KBSI), grant (No. 2023R1A6C101B022), funded by the Ministry of Education. Additional support was provided by the KRIBB Research Initiative Program, grant (No. KGM5322523), and the Mid-career Faculty Research Support Grant at Changwon National University in 2024.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

References

Crescitelli

Lässer

Szabó

, et al. Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes. J Extracell Vesicles 2013; 2. DOI: https://doi.org/10.3402/jev.v2i0.20677

Théry

Zitvogel

Amigorena

. Exosomes: composition, biogenesis and function. Nat Rev Immunol 2002; 2: 569–579.

Zhang

Lee

Zhu

, et al. Enrichment of selective miRNAs in exosomes and delivery of exosomal miRNAs in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol 2017; 312: L110–l121.

Raposo

Stoorvogel

. Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 2013; 200: 373–383.

Lee

Zhang

, et al. Caveolin-1 selectively regulates microRNA sorting into microvesicles after noxious stimuli. J Exp Med 2019; 216: 2202–2220.

Liang

, et al. Osteoclast-derived apoptotic bodies couple bone resorption and formation in bone remodeling. Bone Res 2021; 9: 5.

Zhu

Zhang

Lee

, et al. Macrophage-derived apoptotic bodies promote the proliferation of the recipient cells via shuttling microRNA-221/222. J Leukocyte Biol 2017; 101: 1349–1359.

Yáñez-Mó

Siljander

Andreu

, et al. Biological properties of extracellular vesicles and their physiological functions. J Extracell Vesicles 2015; 4: 27066.

Buzas

. The roles of extracellular vesicles in the immune system. Nat Rev Immunol 2023; 23: 236–250.

10.

Zhang

Zhu

Xie

, et al. Extracellular vesicle-packaged PD-L1 impedes macrophage-mediated antibacterial immunity in preexisting malignancy. Cell Rep 2024; 43: 114903.

11.

Wang

, et al. The negative effects of extracellular vesicles in the immune system. Front Immunol 2024; 15: 1410273.

12.

Kumar

Baba

Sadida

, et al. Extracellular vesicles as tools and targets in therapy for diseases. Signal Transduction Targeted Ther 2024; 9: 27.

13.

Kuravi

Harrison

Rainger

, et al. Ability of platelet-derived extracellular vesicles to promote neutrophil-endothelial cell interactions. Inflammation 2019; 42: 290–305.

14.

Mahmoudi

Taghavi-Farahabadi

Namaki

, et al. Exosomes derived from mesenchymal stem cells improved function and survival of neutrophils from severe congenital neutropenia patients in vitro. Hum Immunol 2019; 80: 990–998.

15.

Munich

Sobo-Vujanovic

Buchser

, et al. Dendritic cell exosomes directly kill tumor cells and activate natural killer cells via TNF superfamily ligands. Oncoimmunology 2012; 1: 1074–1083.

16.

Lugini

Cecchetti

Huber

, et al. Immune surveillance properties of human NK cell-derived exosomes. J Immunol 2012; 189: 2833–2842.

17.

Skokos

Botros

Demeure

, et al. Mast cell-derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo. J Immunol 2003; 170: 3037–3045.

18.

Gao

Liu

Yuan

, et al. Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF-α mediated NF-κB pathway. J Cell Mol Med 2016; 20: 2318–2327.

19.

Lee

Zhang

Laskin

, et al. Functional evidence of pulmonary extracellular vesicles in infectious and noninfectious lung inflammation. J Immunol 2018; 201: 1500–1509.

20.

Bao

, et al. Alveolar macrophage - derived exosomes modulate severity and outcome of acute lung injury. Aging 2020; 12: 6120–6128.

21.

Skokos

Le Panse

Villa

, et al. Mast cell-dependent B and T lymphocyte activation is mediated by the secretion of immunologically active exosomes. J Immunol 2001; 166: 868–876.

22.

Al-Nedawi

Szemraj

Cierniewski

. Mast cell-derived exosomes activate endothelial cells to secrete plasminogen activator inhibitor type 1. Arterioscler, Thromb, Vasc Biol 2005; 25: 1744–1749.

23.

Rossaint

Kühne

Skupski

, et al. Directed transport of neutrophil-derived extracellular vesicles enables platelet-mediated innate immune response. Nat Commun 2016; 7: 13464.

24.

Singhto

Thongboonkerd

. Exosomes derived from calcium oxalate-exposed macrophages enhance IL-8 production from renal cells, neutrophil migration and crystal invasion through extracellular matrix. J Proteomics 2018; 185: 64–76.

25.

Taghavi-Farahabadi

Mahmoudi

Mahdaviani

, et al. Improving the function of neutrophils from chronic granulomatous disease patients using mesenchymal stem cells’ exosomes. Hum Immunol 2020; 81: 614–624.

26.

Wang

Börger

Sardari

, et al. Mesenchymal stromal cell-derived small extracellular vesicles induce ischemic neuroprotection by modulating leukocytes and specifically neutrophils. Stroke 2020; 51: 1825–1834.

27.

Leal

Mizurini

Gomes

, et al. Tumor-Derived exosomes induce the formation of neutrophil extracellular traps: implications for the establishment of cancer-associated thrombosis. Sci Rep 2017; 7: 6438.

28.

Vargas

Roux-Dalvai

Droit

, et al. Neutrophil-Derived exosomes: a new mechanism contributing to airway smooth muscle remodeling. Am J Respir Cell Mol Biol 2016; 55: 450–461.

29.

Zhu

Wang

, et al. LncRNA HCG18 loaded by polymorphonuclear neutrophil-secreted exosomes aggravates sepsis acute lung injury by regulating macrophage polarization. Clin Hemorheol Microcirc 2023; 85: 13–30.

30.

Jiao

Zhang

, et al. Exosomal miR-30d-5p of neutrophils induces M1 macrophage polarization and primes macrophage pyroptosis in sepsis-related acute lung injury. Crit Care 2021; 25: 56.

31.

Eken

Martin

Sadallah

, et al. Ectosomes released by polymorphonuclear neutrophils induce a MerTK-dependent anti-inflammatory pathway in macrophages. J Biol Chem 2010; 285: 39914–39921.

32.

Szatmary

Nossal

Parent

, et al. Modeling neutrophil migration in dynamic chemoattractant gradients: assessing the role of exosomes during signal relay. Mol Biol Cell 2017; 28: 3457–3470.

33.

Zhang

, et al. Engineered neutrophil-derived exosome-like vesicles for targeted cancer therapy. Sci Adv 2022; 8: eabj8207.

34.

Markova

Mikhailova

Milyutina

, et al. Effects of microvesicles derived from NK cells stimulated with IL-1β on the phenotype and functional activity of endothelial cells. Int J Mol Sci 2021; 22: 13663.

35.

Jong

, et al. Large-scale isolation and cytotoxicity of extracellular vesicles derived from activated human natural killer cells. J Extracell Vesicles 2017; 6: 1294368.

36.

Choi

Lim

Kang

, et al. Proteome analysis of human natural killer cell derived extracellular vesicles for identification of anticancer effectors. Molecules 2020; 25: 5216.

37.

Zhu

Kalimuthu

Gangadaran

, et al. Exosomes derived from natural killer cells exert therapeutic effect in melanoma. Theranostics 2017; 7: 2732–2745.

38.

Di Pace

Tumino

Besi

, et al. Characterization of human NK cell-derived exosomes: role of DNAM1 receptor in exosome-mediated cytotoxicity against tumor. Cancers (Basel) 2020; 12: 61.

39.

Federici

Shahaj

Cecchetti

, et al. Natural-Killer-Derived extracellular vesicles: immune sensors and interactors. Front Immunol 2020; 11: 62.

40.

, et al. Immunoregulatory functions and therapeutic potential of natural killer cell-derived extracellular vesicles in chronic diseases. Front Immunol 2023; 14: 1328094.

41.

Sokolov

Gorshkova

Markova

, et al. Natural killer cell derived microvesicles affect the function of trophoblast cells. Membranes 2023; 13: 13.

42.

Wang

Jin

, et al. NK cell-derived exosomes carry miR-207 and alleviate depression-like symptoms in mice. J Neuroinflammation 2020; 17: 26.

43.

Wang

Chen

, et al. Natural killer cell-derived exosomal miR-1249-3p attenuates insulin resistance and inflammation in mouse models of type 2 diabetes. Signal Transduction Targeted Ther 2021; 6: 09.

44.

Dosil

Lopez-Cobo

Rodriguez-Galan

, et al. Natural killer (NK) cell-derived extracellular-vesicle shuttled microRNAs control T cell responses. eLife 2022; 11. DOI: https://doi.org/10.7554/eLife.76319

45.

Wang

Quan

. Exosomes derived from natural killer cells inhibit hepatic stellate cell activation and liver fibrosis. Hum Cell 2020; 33: 582–589.

46.

Di Pace

Pelosi

Fiore

, et al. MicroRNA analysis of natural killer cell-derived exosomes: the microRNA let-7b-5p is enriched in exosomes and participates in their anti-tumor effects against pancreatic cancer cells. Oncoimmunology 2023; 12: 2221081.

47.

Sun

Shi

, et al. Natural killer cell-derived exosomal miR-3607-3p inhibits pancreatic cancer progression by targeting IL-26. Front Immunol 2019; 10: 2819.

48.

Neviani

Wise

Murtadha

, et al. Natural killer-derived exosomal miR-186 inhibits neuroblastoma growth and immune Escape mechanisms. Cancer Res 2019; 79: 1151–1164.

49.

Enomoto

Jenkins

, et al. Cytokine-enhanced cytolytic activity of exosomes from NK cells. Cancer Gene Ther 2022; 29: 734–749.

50.

Kim

Song

, et al. Functional enhancement of exosomes derived from NK cells by IL-15 and IL-21 synergy against hepatocellular carcinoma cells: the cytotoxicity and apoptosis in vitro study. Heliyon 2023; 9: e16962.

51.

Whiteside

. Immune modulation of T-cell and NK (natural killer) cell activities by TEXs (tumour-derived exosomes). Biochem Soc Trans 2013; 41: 245–251.

52.

Liu

Zinn

, et al. Murine mammary carcinoma exosomes promote tumor growth by suppression of NK cell function. J Immunol 2006; 176: 1375–1385.

53.

Huyan

Gao

, et al. miR-221-5p and miR-186-5p are the critical bladder cancer derived exosomal miRNAs in natural killer cell dysfunction. Int J Mol Sci 2022; 23: 15177.

54.

Shoae-Hassani

Hamidieh

Behfar

, et al. NK Cell-derived exosomes from NK cells previously exposed to neuroblastoma cells augment the antitumor activity of cytokine-activated NK cells. J Immunother 2017; 40: 265–276.

55.

Zhang

Gao

Huang

, et al. Cancer cell-derived exosomal circUHRF1 induces natural killer cell exhaustion and may cause resistance to anti-PD1 therapy in hepatocellular carcinoma. Mol Cancer 2020; 19: 10.

56.

Ahmadi

Abbasi

Rezaie

. Tumor immune escape: extracellular vesicles roles and therapeutics application. Cell Commun Signaling 2024; 22: 9.

57.

Liu

, et al. Tumor exosomes inhibit differentiation of bone marrow dendritic cells. J Immunol 2007; 178: 6867–6875.

58.

Salimu

Webber

Gurney

, et al. Dominant immunosuppression of dendritic cell function by prostate-cancer-derived exosomes. J Extracell Vesicles 2017; 6: 1368823.

59.

Gassmann

Schneider

Evdokimova

, et al. Ewing sarcoma-derived extracellular vesicles impair dendritic cell maturation and function. Cells 2021; 10: 2081.

60.

Paixão

Teixeira

Rodrigues

. Zika, chikungunya and dengue: the causes and threats of new and re-emerging arboviral diseases. BMJ global Health 2018; 3: e000530.

61.

Martins

Kuczera

Lötvall

, et al. Characterization of dendritic cell-derived extracellular vesicles during dengue virus infection. Front Microbiol 2018; 9: 1792.

62.

Izquierdo-Serrano

Fernández-Delgado

Moreno-Gonzalo

, et al. Extracellular vesicles from Listeria monocytogenes-infected dendritic cells alert the innate immune response. Front Immunol 2022; 13: 946358.

63.

Elsayed

Elashiry

Liu

, et al. Porphyromonas gingivalis provokes exosome secretion and paracrine immune senescence in bystander dendritic cells. Front Cell Infect Microbiol 2021; 11: 669989.

64.

Elsayed

Elashiry

Liu

, et al. Microbially-Induced exosomes from dendritic cells promote paracrine immune senescence: novel mechanism of bone degenerative disease in mice. Aging Dis 2023; 14: 136–151.

65.

Giri

Schorey

. Exosomes derived from M. Bovis BCG infected macrophages activate antigen-specific CD4+ and CD8+ T cells in vitro and in vivo. PloS one 2008; 3: e2461.

66.

Reis

Mavin

Nicholson

, et al. Mesenchymal stromal cell-derived extracellular vesicles attenuate dendritic cell maturation and function. Front Immunol 2018; 9: 2538.

67.

Zitvogel

Regnault

Lozier

, et al. Eradication of established murine tumors using a novel cell-free vaccine: dendritic cell-derived exosomes. Nat Med 1998; 4: 594–600.

68.

Viaud

Terme

Flament

, et al. Dendritic cell-derived exosomes promote natural killer cell activation and proliferation: a role for NKG2D ligands and IL-15Ralpha. PloS one 2009; 4: e4942.

69.

Jung

Shin

Baek

, et al. Modification of immune cell-derived exosomes for enhanced cancer immunotherapy: current advances and therapeutic applications. Exp Mol Med 2024; 56: 19–31.

70.

Yao

Zhou

, et al. DC-Derived Exosomes for cancer immunotherapy. Cancers (Basel) 2021; 13: 3667.

71.

Zhou

, et al. DC-Based Vaccines for cancer immunotherapy. Vaccines (Basel) 2020; 8: 06.

72.

Zhou

, et al. Plasmacytoid dendritic cells and cancer immunotherapy. Cells 2022; 11: 22.

73.

Del Prete

Salvi

Soriani

, et al. Dendritic cell subsets in cancer immunity and tumor antigen sensing. Cell Mol Immunol 2023; 20: 432–447.

74.

Huang

Rong

Tang

, et al. Engineered exosomes as an in situ DC-primed vaccine to boost antitumor immunity in breast cancer. Mol Cancer 2022; 21: 45.

75.

Lee

Groot

Pinilla-Vera

, et al. Identification of miRNA-rich vesicles in bronchoalveolar lavage fluid: insights into the function and heterogeneity of extracellular vesicles. J Controlled Release 2019; 294: 43–52.

76.

Lee

Zhang

, et al. Lung epithelial cell-derived microvesicles regulate macrophage migration via MicroRNA-17/221-induced integrin β(1) recycling. J Immunol 2017; 199: 1453–1464.

77.

Lee

Zhang

Zhu

, et al. Epithelial cell-derived microvesicles activate macrophages and promote inflammation via microvesicle-containing microRNAs. Sci Rep 2016; 6: 35250.

78.

Jiao

Loughran

, et al. Frontline science: macrophage-derived exosomes promote neutrophil necroptosis following hemorrhagic shock. J Leukocyte Biol 2018; 103: 175–183.

79.

Zhang

Gao

Qin

, et al. Inflammatory alveolar macrophage-derived microvesicles damage lung epithelial cells and induce lung injury. Immunol Lett 2022; 241: 23–34.

80.

Wang

Huang

, et al. Exosomes from M1-polarized macrophages enhance paclitaxel antitumor activity by activating macrophages-mediated inflammation. Theranostics 2019; 9: 1714–1727.

81.

Ding

Zhang

Cai

, et al. Extracellular vesicles derived from M1 macrophages deliver miR-146a-5p and miR-146b-5p to suppress trophoblast migration and invasion by targeting TRAF6 in recurrent spontaneous abortion. Theranostics 2021; 11: 5813–5830.

82.

Zhang

Tao

Cai

, et al. miR-196a-5p-Rich extracellular vesicles from trophoblasts induce M1 polarization of macrophages in recurrent miscarriage. J Immunol Res 2022; 2022: 6811632.

83.

Wang

Zhao

, et al. Circube3a from M2 macrophage-derived small extracellular vesicles mediates myocardial fibrosis after acute myocardial infarction. Theranostics 2021; 11: 6315–6333.

84.

Yuan

Liang

Liu

, et al. Mechanism of miR-378a-3p enriched in M2 macrophage-derived extracellular vesicles in cardiomyocyte pyroptosis after MI. Hypertens Res 2022; 45: 650–664.

85.

Wang

Lin

Zhang

, et al. M2 macrophage-derived exosomes promote diabetic fracture healing by acting as an immunomodulator. Bioact Mater 2023; 28: 273–283.

86.

Gao

Jin

Tan

, et al. Erythrocyte-derived extracellular vesicles aggravate inflammation by promoting the proinflammatory macrophage phenotype through TLR4-MyD88-NF-κB-MAPK pathway. J Leukocyte Biol 2022; 112: 693–706.

87.

Sun

Liu

, et al. hUC-EVs-ATO reduce the severity of acute GVHD by resetting inflammatory macrophages toward the M2 phenotype. J Hematol Oncol 2022; 15: 99.

88.

Zheng

Luo

Wang

, et al. Tumor-associated macrophages-derived exosomes promote the migration of gastric cancer cells by transfer of functional apolipoprotein E. Cell Death Dis 2018; 9: 34.

89.

Lan

Sun

, et al. M2 macrophage-derived exosomes promote cell migration and invasion in colon cancer. Cancer Res 2019; 79: 146–158.

90.

Wei

Yang

, et al. M2 macrophage-derived exosomes promote lung adenocarcinoma progression by delivering miR-942. Cancer Lett 2022; 526: 205–216.

91.

Guan

Dai

Zhu

, et al. M2 macrophage-derived exosomal miR-1911-5p promotes cell migration and invasion in lung adenocarcinoma by down-regulating CELF2 -activated ZBTB4 expression. Anti-cancer Drugs 2023; 34: 238–247.

92.

McDonald

Tian

Qureshi

, et al. Functional significance of macrophage-derived exosomes in inflammation and pain. Pain 2014; 155: 1527–1539.

93.

Reed

Schorey

D'Souza-Schorey

. Tumor-Derived extracellular vesicles: a means of co-opting macrophage polarization in the tumor microenvironment. Front Cell Dev Biol 2021; 9: 746432.

94.

Chen

Gao

Tong

, et al. Crosstalk between extracellular vesicles and tumor-associated macrophage in the tumor microenvironment. Cancer Lett 2023; 552: 215979.

95.

Chen

Zhang

Zhi

, et al. Tumor-derived exosomal miR-19b-3p facilitates M2 macrophage polarization and exosomal LINC00273 secretion to promote lung adenocarcinoma metastasis via hippo pathway. Clin Transl Med 2021; 11: e478.

96.

Fan

Wang

, et al. Mesenchymal stem cell-derived extracellular vesicles in liver immunity and therapy. Front Immunol 2022; 13: 833878.

97.

Yan

Huang

, et al. Anti-inflammatory and immunomodulatory effects of the extracellular vesicles derived from human umbilical cord mesenchymal stem cells on osteoarthritis via M2 macrophages. J Nanobiotechnol 2022; 20: 38.

98.

Yuan

Yang

Luo

, et al. MicroRNA-204 carried by exosomes of human umbilical cord-derived mesenchymal stem cells regulates the polarization of macrophages in a mouse model of myocardial ischemia-reperfusion injury. Zhongguo yi xue ke xue Yuan xue bao Acta Academiae Medicinae Sinicae 2022; 44: 785–793.

99.

Liu

Xiao

Xie

. Advances in the regulation of macrophage polarization by mesenchymal stem cells and implications for ALI/ARDS treatment. Front Immunol 2022; 13: 928134.

100.

Willis

Fernandez-Gonzalez

Reis

, et al.

Macrophage immunomodulation: the gatekeeper for mesenchymal stem cell derived-exosomes in pulmonary arterial hypertension?

Int J Mol Sci 2018; 19: 2534.

101.

Hwang

Sung

Kim

, et al. Mesenchymal stromal cells primed by toll-like receptors 3 and 4 enhanced anti-inflammatory effects against LPS-induced macrophages via extracellular vesicles. Int J Mol Sci 2023; 24: 16264.

102.

Bhatnagar

Schorey

. Exosomes released from infected macrophages contain Mycobacterium avium glycopeptidolipids and are proinflammatory. J Biol Chem 2007; 282: 25779–25789.

103.

Kim

Lee

Bae

, et al. Lactobacillus plantarum-derived extracellular vesicles induce anti-inflammatory M2 macrophage polarization in vitro. J Extracell Vesicles 2020; 9: 1793514.

104.

Nolte-'t Hoen

Buschow

Anderton

, et al. Activated T cells recruit exosomes secreted by dendritic cells via LFA-1. Blood 2009; 113: 1977–1981.

105.

Admyre

Bohle

Johansson

, et al. B cell-derived exosomes can present allergen peptides and activate allergen-specific T cells to proliferate and produce TH2-like cytokines. J Allergy Clin Immunol 2007; 120: 1418–1424.

106.

Leone

Rees

Kain

. Dendritic cells and routing cargo into exosomes. Immunol Cell Biol 2018; 96: 683–693.

107.

Robbins

Morelli

. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol 2014; 14: 195–208.

108.

Qiu

Zhou

Zhang

, et al. Exosome: the regulator of the immune system in sepsis. Front Pharmacol 2021; 12: 671164.

109.

Théry

Duban

Segura

, et al. Indirect activation of naïve CD4+ T cells by dendritic cell-derived exosomes. Nat Immunol 2002; 3: 1156–1162.

110.

Chaput

Théry

. Exosomes: immune properties and potential clinical implementations. Semin Immunopathol 2011; 33: 419–440.

111.

Vincent-Schneider

Stumptner-Cuvelette

Lankar

, et al. Exosomes bearing HLA-DR1 molecules need dendritic cells to efficiently stimulate specific T cells. Int Immunol 2002; 14: 713–722.

112.

Duneton

Winterberg

Ford

. Activation and regulation of alloreactive T cell immunity in solid organ transplantation. Nat Rev Nephrol 2022; 18: 663–676.

113.

Shenoda

Ajit

. Modulation of immune responses by exosomes derived from antigen-presenting cells. Clin Med Insights Pathol 2016; 9s1: –8.

114.

André

Chaput

Schartz

, et al. Exosomes as potent cell-free peptide-based vaccine. I. Dendritic cell-derived exosomes transfer functional MHC class I/peptide complexes to dendritic cells. J Immunol 2004; 172: 2126–2136.

115.

Balan

Bhardwaj

. Cross-Presentation of tumor antigens is ruled by synaptic transfer of vesicles among dendritic cell subsets. Cancer Cell 2020; 37: 751–753.

116.

Vukman

Ferencz

Fehér

, et al. An implanted device enables in vivo monitoring of extracellular vesicle-mediated spread of pro-inflammatory mast cell response in mice. J Extracell Vesicles 2020; 10: e12023.

117.

Toyoshima

Sakamoto-Sasaki

Kurosawa

, et al. miR103a-3p in extracellular vesicles from FcεRI-aggregated human mast cells enhances IL-5 production by group 2 innate lymphoid cells. J Allergy Clin Immunol 2021; 147: 1878–1891.

118.

Zou

Zhou

Zhang

. MicroRNA-21 released from mast cells-derived extracellular vesicles drives asthma in mice by potentiating airway inflammation and oxidative stress. Am J Transl Res 2021; 13: 7475–7491.

119.

Yin

Shelke

Lässer

, et al. Extracellular vesicles from mast cells induce mesenchymal transition in airway epithelial cells. Respir Res 2020; 21: 01.

120.

Cho

Kwon

Kim

, et al. Mesenchymal stem cell exosomes differentially regulate gene expression of mast cells. Biochem Biophys Res Commun 2024; 696: 149517.

121.

Gorzalczany

Merimsky

Sagi-Eisenberg

. Mast cells are directly activated by cancer cell-derived extracellular vesicles by a CD73- and adenosine-dependent mechanism. Transl Oncol 2019; 12: 1549–1556.

122.

Shefler

Salamon

Zitman-Gal

, et al. Tumor-Derived extracellular vesicles induce CCL18 production by mast cells: a possible link to angiogenesis. Cells 2022; 11: 53.

123.

Ben

Huang

Shi

, et al. Change in cytokine profiles released by mast cells mediated by lung cancer-derived exosome activation may contribute to cancer-associated coagulation disorders. Cell Commun Signaling 2023; 21: 97.

124.

Shemesh

Laufer-Geva

Gorzalczany

, et al. The interaction of mast cells with membranes from lung cancer cells induces the release of extracellular vesicles with a unique miRNA signature. Sci Rep 2023; 13: 21544.

125.

Jia

Cui

, et al. NK cell-derived exosomes improved lung injury in mouse model of Pseudomonas aeruginosa lung infection. J Physiol Sci 2020; 70: 50.

126.

Xiao

Lässer

Shelke

, et al. Mast cell exosomes promote lung adenocarcinoma cell proliferation - role of KIT-stem cell factor signaling. Cell Commun Signaling 2014; 12: 64.

127.

Chew

Hou

, et al. Microvesicles from malaria-infected red blood cells activate natural killer cells via MDA5 pathway. PLoS Pathog 2018; 14: e1007298.

128.

Kim

Park

Dinh

NTH

, et al. Bacterial outer membrane vesicles suppress tumor by interferon-γ-mediated antitumor response. Nat Commun 2017; 8: 26.

129.

Kouwaki

Fukushima

Daito

, et al. Extracellular vesicles including exosomes regulate innate immune responses to hepatitis B virus infection. Front Immunol 2016; 7: 35.

130.

Yang

Han

Hou

, et al. Exosomes mediate hepatitis B virus (HBV) transmission and NK-cell dysfunction. Cell Mol Immunol 2017; 14: 465–475.

131.

Souza

JAM

Baltazar

Carregal

, et al. Characterization of Aspergillus fumigatus extracellular vesicles and their effects on macrophages and neutrophils functions. Front Microbiol 2019; 10: 2008.

Biological significance of extracellular vesicles in innate immune system

Abstract

Keywords

Introduction

Neutrophils and EVs

Natural killer cells and EVs

Dendritic cells and EVs: orchestrating immune responses

Macrophages and EVs: orchestrating inflammatory responses

Antigen presenting cells and EVs: bridging innate and adaptive immunity

Mast cells and EVs: unraveling the intricacies of immune regulation

Conclusions: unveiling the potential of EVs in innate immunity

Footnotes

Acknowledgement

ORCID iDs

Author contributions

Funding

Declaration of conflicting interests

References