Extracellular Vesicles in Asthma: Intercellular Cross-Talk in TH2 Inflammation
Abstract
:1. Introduction
2. The Cellular Drivers in Asthma Inflammation and EVs’ Related Role
2.1. TH2-High Asthma-Related Cells
2.1.1. Epithelial Cell-Derived EVs
2.1.2. Eosinophilic-Derived EVs
2.1.3. Lymphocyte-Derived EVs
2.1.4. Mast Cell-Derived EVs
2.1.5. Dendritic Cell-Derived EVs
2.2. TH2-Low Asthma-Related Cells
2.2.1. Neutrophil-Derived EVs
2.2.2. Macrophage-Derived EVs
3. The Paradigm of Mesenchymal Stem Cell-Derived EVs
Cell Type | Main Findings | References |
---|---|---|
Epithelial cells | Exosomes derived from AECs can cause inflammation by increasing IL-8 and LTC4. | [31] |
BECs play a pivotal role in exosome-driven cell-to-cell communication and promote the proliferation and infiltration of undifferentiated macrophages. | [43] | |
AEC-derived exosomes with intertwined filamentous formations on their surface lead to airway inflammation remodeling. | [44] | |
Exosomes secreted by OVA-induced AECs promote CD4+ T cell differentiation in Th2-like cells. | [45] | |
AEC-derived exosomes with CNTN1 protein play a significant role in modulating allergic responses via DCs. | [46] | |
Mechanical stress leads to TF expression and its transport via exosomes in normal BECs. | [47] | |
Exosomes can transport TF between different cells, linking it to asthma. | [48,49] | |
TF expression levels were higher in asthmatic patients, and TGF-β plays an important role in asthma mechanical stress. | [50] | |
TGF-β2 expression in exosomes was reduced in severe asthmatic patients. | [51,52] | |
TGF-β2 secreted from exosomes has a regulatory effect in cell proliferation. | [52] | |
Epithelium-derived exosomes secrete miRNA involved in asthma development. | [53] | |
MiR-34a regulates the functions of dendritic cells and their maturation, targeting the Wnt pathway. | [54] | |
MiR-92b is involved in epithelial-to-mesenchymal transition. | [55] | |
Eosinophils | Eosinophil-derived exosomes mediate immune responses and structural changes. | [60,61] |
Eosinophil-derived exosomes significantly influence asthma pathogenesis. | [36] | |
EVs from the eosinophils of asthmatic patients increase NO and ROS production. Patients enhance chemotaxis, upregulate cell adhesion molecules, and upregulate integrin α2 in eosinophils. | [62,63] | |
EVs from eosinophils contribute to the inflammatory response and structural changes in the lungs. | [64,65] | |
Eosinophil-derived exosomes alter gene expression in various cell types, including lung cells, contributing to asthma pathology. | [63,64] | |
Eosinophils express exosomal markers such as CD63 and CD9. | [66] | |
The stimulation of eosinophils with IFN-γ enhanced exosome production, particularly in asthma patients. | [61] | |
Eosinophils from asthmatic patients have a greater production of exosomes. | [63] | |
Eosinophil-derived exosomes promote inflammation related with asthma. | [68] | |
Eosinophil-derived exosomes contribute to airway structural changes. | [64] | |
Lymphocytes | B cell-derived exosomes exhibit the features of their originating cells and present HSP70, important for DC maturation. | [72,74] |
B cell-derived exosomes can present antigen peptides to T cells, inducing the release of proinflammatory cytokines. | [73] | |
Antigen-presenting cell (APC)-derived exosomes are significant contributors to T cell activation. | [75] | |
Two mechanisms through which B cell-derived exosomes activate T cells are direct stimulation and through the involvement of APC. | [76,77,78] | |
B lymphocyte-produced exosomes stimulate the release of cytokines IL-5 and IL-13. | [80,81] | |
Activated T cells release exosomes upon activation. | [29,82] | |
T cell-derived exosomes trigger mast cell activation and degranulation, cytokine release, tissue remodeling, and increasing airway reactivity. | [83] | |
T cell-derived exosomes inhibit CD8+ T lymphocyte activity. | [84] | |
T cell-derived exosomes shape an optimal environment for immune cell operations, mediating communications to enhance immune response. | [59,85] | |
T cell EVs are able to activate MC degranulation and the release of cytokines. | [86] | |
Th2 cells promote eosinophil survival through the inhibition of apoptosis. | [87] | |
Mast cells | MC-derived exosomes carry immune-related factors, which play an important role in immunity. | [92,93] |
Mast cell-derived exosomes secrete miR-21, which promotes oxidative stress and inflammation in asthmatic mice. | [94] | |
BMMC-derived exosomes could activate immune cells without direct contact, suggesting the mobilization of B and T cells into lungs. | [95] | |
MCs can exchange RNA with each other through EVs. | [96] | |
MC-derived exosomes enhance the ability of DCs to present antigens to T cells and regulate T lymphocyte activation. | [29] | |
BMMC-derived exosomes are able to lower IgE levels and block mast cell activation. | [97] | |
MC-derived EVs convey a protective message under oxidative stress, decreasing mortality. | [98] | |
miR-21 released from MC-derived exosomes enhances oxidative stress and triggers inflammatory reactions in asthmatic mice. | [94] | |
Exosomes activated by IgE from MCs exacerbate atherosclerosis by inducing endothelial dysfunction through the circular RNA CDR1as, linking asthma with atherosclerosis. | [99] | |
Dendritic cells | DC-derived exosomes can activate allergen-specific Th2 cells. | [29] |
DC exosomes specifically activate OVA-targeted CD8+ T cells and promote OVA-specific IgG antibody production. | [104] | |
DC-derived exosomes carry enzymes necessary for producing leukotrienes. | [105,106] | |
DC-derived exosomes, when packed with chemotactic eicosanoids, promote inflammation and granulocyte migration in vitro. | [106] | |
Various subsets of pulmonary DCs have been identified, each contributing differently to asthma pathogenesis. | [107,108] | |
Neutrophils | Neutrophil-derived exosomes play a role in regulating changes in airway smooth muscle structure. | [113,114] |
OVA-induced airway epithelium-derived exosomes increase AHR and trigger the accumulation/activation of macrophages, neutrophils, and eosinophils. | [115] | |
Neutrophil-derived EVs disrupt epithelial cell connections. | [116] | |
Exosomes released by neutrophils contribute to airway structural changes, promoting the migration and proliferation of ASMCs in response to LPS. | [117] | |
Neutrophil-derived exosomes containing elastase contribute significantly to airway inflammation. | [118] | |
Macrophages | Macrophage-derived exosomes have a significant impact on T1 immune reactions. | [126,127] |
In SSRA, M1 macrophages release high levels of inflammatory molecules, contributing to neutrophil-rich infiltration, AHR, and airway structural changes. | [128] | |
Exosomes secreted from human macrophages have a proinflammatory role in asthma and contain enzymes that favor LTC4 production. | [106] | |
Exosomes secreted by M2 macrophages reduce lung inflammation and asthma progression through the action of miR-370. | [129] | |
Mesenchymal stem cells | MSC-EVs exhibit therapeutic effects similar to MSCs but with reduced risks of immune rejection, tumorigenicity, and pulmonary embolism. | [131] |
EVsderived from mesenchymal stem cells have a similar therapeutic effect to their parental cells. | [132] | |
EVsderived from mesenchymal stem cells impact immune cells and inhibit airway remodeling. | [13] | |
ASCs and other MSCs can reduce allergic airway inflammation in bronchial asthma mouse models. | [133] | |
ASC-derived EVs immunomodulatory effects are thought to involve the suppression of Th2 cytokine production in airway allergic inflammation. | [134] | |
AD-MSC-derived exosomes showed beneficial effects on ovalbumin-induced allergic asthma. | [135] | |
MSC-derived extracellular vesicles have been proposed as a promising alternative to MSCs for treatments such as asthma. | [136] | |
BMMC-derived exosomes highly expressed a specific miRNA, miR-223-3p, known to be associated with high inflammation and the exacerbation of asthma. | [137] | |
MSC-derived exosomal miR-1470 induces the expression of P27KIP1 in asthmatic patients, promoting the differentiation of CD4+CD25+FOXP3+ Tregs. | [138] | |
BMMC-derived exosomes contain miR-188, which has a negative effect on airway remodeling and lung injury. | [139] | |
hUCMSC-derived EVs have a therapeutic effect in SSRA, with an action on the NF-kB and PI3K/AKT signaling pathways. | [140] | |
Migrasomes secreted from hUCMSCs play a role in the protective effect of hUCMSCs in asthma. | [141] | |
Hypo-EVs are able to reduce airway inflammation and remodeling in asthmatic mice. | [142] | |
Hypo-EVs have a therapeutic effect on epithelial barriers both in vivo and in vitro. | [143] | |
The therapeutic mechanisms of MSC-EVs can be categorized into several key pathways in the context of asthma treatment. | [144] |
4. Methods for EVs Analysis: Available Tools, Potential, and Challenges
5. Discussion
6. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AD-MSCs | Adipose tissue-derived mesenchymal stromal cell |
AERD | Aspirin-exacerbated respiratory disease |
AHR | Airway hyperresponsiveness |
APC | Antigen-presenting cell |
ASCs | Adipose-derived stem cells |
ASM | Airway smooth muscle |
BALF | Bronchoalveolar lavage fluid |
BECs | Bronchial epithelial cells |
BMMCs | Bone marrow-derived mesenchymal stem cells |
BSMCs | Bronchial smooth muscle cells |
circ | Circular |
cysLT | Cysteinyl leukotrienes |
DCs | Dendritic cells |
DRMs | Detergent-resistant membrane microdomains |
ECP | Eosinophil cationic protein |
EDN | Eosinophil-derived neurotoxin |
EPX | Eosinophil peroxidase |
ETM | Epithelial-to-mesenchymal transition |
EVs | Extracellular vesicles |
FeNO | Nitric oxide |
FGM1 | Fibroblast growth factor 1 |
GM-CSF | Granulocyte–macrophage colony-stimulating factor |
hUCMSCs | Human umbilical cord mesenchymal stem cells |
Hypo-EVs | Hypoxic hUCMSC-EVs |
IFN-γ | Interferon-gamma |
IgE | Immunoglobulin E |
ISEV | International Society for Extracellular Vesicles |
LAMP1 | Liposomal-associated membrane protein 1 |
LFA1 | Lymphocyte function-associated antigen-1 |
lnc | Long noncoding |
LPS | Lipopolysaccharide |
MBP | Major basic protein |
MCs | Mast cells |
MHC | Major histocompatibility complex |
miRNAs | MicroRNAs |
MSC-EVs | MSC-derived extracellular vesicles |
MSCs | Mesenchymal stem cells |
NHBE | Normal human bronchial epithelial cells |
NO | Nitric oxide |
NTA | Nanoparticle tracking analysis |
PDCs | Plasmacytoid |
PS | Phosphatidylserine |
ROS | Reactive oxygen species |
SSRA | Severe steroid-resistant asthma |
TCR | T cell receptor |
TEM | Transmission electron microscopy |
TF | Tissue factor |
Tregs | Regulatory T cells |
UCMSC-EVs | Umbilical cord mesenchymal stem cell-derived EVs |
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Cheema, N.A.; Castagna, A.; Ambrosani, F.; Argentino, G.; Friso, S.; Zurlo, M.; Beri, R.; Maule, M.; Vaia, R.; Senna, G.; et al. Extracellular Vesicles in Asthma: Intercellular Cross-Talk in TH2 Inflammation. Cells 2025, 14, 542. https://doi.org/10.3390/cells14070542
Cheema NA, Castagna A, Ambrosani F, Argentino G, Friso S, Zurlo M, Beri R, Maule M, Vaia R, Senna G, et al. Extracellular Vesicles in Asthma: Intercellular Cross-Talk in TH2 Inflammation. Cells. 2025; 14(7):542. https://doi.org/10.3390/cells14070542
Chicago/Turabian StyleCheema, Naila Arif, Annalisa Castagna, Francesca Ambrosani, Giuseppe Argentino, Simonetta Friso, Marco Zurlo, Ruggero Beri, Matteo Maule, Rachele Vaia, Gianenrico Senna, and et al. 2025. "Extracellular Vesicles in Asthma: Intercellular Cross-Talk in TH2 Inflammation" Cells 14, no. 7: 542. https://doi.org/10.3390/cells14070542
APA StyleCheema, N. A., Castagna, A., Ambrosani, F., Argentino, G., Friso, S., Zurlo, M., Beri, R., Maule, M., Vaia, R., Senna, G., & Caminati, M. (2025). Extracellular Vesicles in Asthma: Intercellular Cross-Talk in TH2 Inflammation. Cells, 14(7), 542. https://doi.org/10.3390/cells14070542