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Extracellular Vesicles as Unique Signaling Messengers: Role in Lung Diseases

Yuansheng Gao, J. Usha Raj

10.1002/cphy.c200006

Source: Volume 11, Issue 1, January 2021

Published online: December 2020

Full Article on Wiley Online Library



Abstract

Extracellular vesicles (EVs) are lipid bilayer‐enclosed extracellular particles carrying rich cargo such as proteins, lipids, and microRNAs with distinct characteristics of their parental cells. EVs are emerging as an important form of cellular communication with the ability to selectively deliver a kit of directional instructions to nearby or distant cells to modulate their functions and phenotypes. According to their biogenesis, EVs can be divided into two groups: those of endocytic origin are called exosomes and those derived from outward budding of the plasma membrane are called microvesicles (also known as ectosomes or microparticles). Under physiological conditions, EVs are actively involved in maintenance of pulmonary hemostasis. However, EVs can contribute to the pathogenesis of diseases such as chronic obstructive pulmonary disease, asthma, acute lung injury/acute respiratory distress syndrome, interstitial lung disease, and pulmonary arterial hypertension. EVs, especially those derived from mesenchymal/stromal stem cells, can also be beneficial and can curb the development of lung diseases. Novel technologies are continuously being developed to minimize the undesirable effects of EVs and also to engineer EVs so that they may have beneficial effects and can be used as therapeutic agents in lung diseases. © 2021 American Physiological Society. Compr Physiol 11:1351‐1369, 2021.

Figure 1. Figure 1. Possible mechanisms of the biogenesis of exosomes (EXOs) and microvesicles (MVs). The biogenesis of EXOs starts from the early endosomes (EE) derived from the internalized plasma membrane or from the biosynthetic pathway of [the trans‐Golgi network (TGN)]. The cargos on the membrane of the endosomes are sorted, followed by budding inwards and fission into small membrane vesicles known as intraluminal vesicles (ILVs) within the lumen of endosomes during their maturation into multivesicular bodies (MVBs). These processes are conducted in a manner dependent or independent of the endosomal sorting complex required for transport (ESCRT) complex. The MVB can either follow a degradation pathway fusing with lysosomes or proceed to release the ILVs as exosomes to the extracellular space. The cytosolic pH may affect MVB function as secretory versus degradatory compartments. For the extracellular release of exosomes, MVBs are first transported to the plasma membranes, a process dependent on the cytoskeleton and regulated by Rab GTPases including Rab27b and Rab35. MVBs are then docked on the plasma membrane that involves the rearrangement of sub‐membrane actin cytoskeleton in a manner depends on Rab27a and Rab11. This is followed by the fusion of MVBs with the plasma membrane that leads to the formation of pores in the membrane to release exosomes. This may be mediated by soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE) proteins and the Ca2+ sensor synaptotagmin (Syt). The microvesicles (MVs) are formed by clustering and sorting of various components in discrete membrane microdomains of the plasma membrane followed by outward budding of the plasma membrane and the release of the MVs. In the clustering and sorting process, ESCRT‐I and tetraspanin may act as key mediators. Concomitant to this process the membrane microdomains of the plasma membrane undergo lipid flipping, that is, exposition of phosphatidylserine and phosphatidylethanolamine from the inner leaflet to the cell surface. Subsequently, the membrane microdomains of the plasma membrane bud outwards and are released as MVs. This process is orchestrated by ESCRT‐III, the small GTPase RhoA and Rho‐associated protein kinase (ROCK) as well as ADP‐ribosylation factor 6 (ARF6), which are involved in actin polymerization and myosin activity in the processes in MV release 61,66,72,73,119,137,141,156,185,187.
Figure 2. Figure 2. Extracellular vesicle (EV) interactions with target cells. EVs can transmit information to target cells by directly binding to cell surface receptors to evoke intracellular signaling without delivery of their content, fusing with the plasma membrane or through endocytosis to deliver their content. The fusion of EVs with the plasma membrane leads to delivery of their content (including protein, peptide, mRNA, miRNA, etc.), which is followed by altered cellular activities including changes in gene transcription. EVs can also be taken up entirely by target cells through various forms of endocytosis. Exosomes and small ectosomes can be internalized via caveolae, clathrin‐coated pits, or lipid rafts; whereas larger ectosomes or aggregated EVs are internalized through phagocytosis or macropinocytosis (a form of endocytosis by which a large fluid‐filled vesicle is pinched off from the cell membrane into the cytoplasm of the cell). The endocytosed EVs are first located in early endosomes (EE). During the maturation of EEs into multivesicular bodies (MVBs), they are transformed into intraluminal vesicles (ILVs) and their intraluminal contents may be released into the cytosol, which is known as back fusion, a process of major importance for delivery of intraluminal cargoes such as miRNAs. EVs may also be degraded when MVBs are fused with the lysosome so that their contents are recycled to fuel the metabolism of the recipient cells 14,26,61,83,84,119,125,147,178,185.
Figure 3. Figure 3. Different signaling pathways mediated by extracellular vesicles (EVs) in the inflammatory response of the lung evoked by infection (lipopolysaccharide/Gram‐negative bacteria) versus oxidative stress (hyperoxia). Infection primarily stimulates alveolar macrophages to release EVs that carry increased levels of microRNA (miR)‐221 and miR‐222 while oxidative stress predominantly stimulates type‐I epithelial cells to release EVs that carry increased levels of miR‐17, miR‐221, miR‐320a. EVs generated in response to infection and oxidative stress both promote the recruitment of macrophages and the development of lung inflammation. However, EVs derived from alveolar macrophages increase the expression of TLR6, MyD88, IL‐1β, IL‐10, and CD80 in recruited alveolar macrophages. By contrast, EVs released from epithelial cells increase the expression of TLR2, MyD88, TNFα, and IL‐6 in recruited alveolar macrophages 10,37,39,100,114,209. CD80, cluster of differentiation 80. IL‐1β, IL‐6, and IL‐10, interleukin‐1β, ‐6, and ‐10, respectively. MyD88, myeloid differentiation factor 88. TLR2 and TLR6, Toll‐like receptor 2, and 6, respectively. TNFα, tumor necrosis factor α.
Figure 4. Figure 4. Possible mechanism for extracellular vesicles (EVs)‐mediated pulmonary vascular remodeling caused by hypoxia and transforming growth factor β (TGF‐β). When exposed to these stimuli pulmonary artery endothelial cells (PAECs) show an increased release of caveolin‐1 positive (Cav‐1+) EVs, which stimulate the production of TGF‐β from macrophages. TGF‐β causes endothelial cells (ECs) to migrate and elicit defective angiogenesis. It also stimulates pulmonary artery smooth muscle cells (PASMCs) to migrate and inhibits their apoptosis. These effects result from the binding to TGF‐β receptors (TGFβR), phosphorylation of Smad2/3, and altered gene expression. The effect of TGF‐β can be counteracted by bone morphogenetic protein (BMP), which inhibits vascular remodeling through binding to BMP receptor type 2 (BMPR2) followed by phosphorylation of Smad1/5/8 and altered gene expression. However, the shedding of Cav‐1+ EVs caused by hypoxia and TGF‐β may lead to dysfunction of endothelial nitric oxide synthase (eNOS) and increased production of peroxynitrite (OONO−), which suppress the expression of BMPR2 and thus vascular remodeling. Under hypoxia and TGF‐β there is also an increased generation of microRNA 143‐3p (miR‐143‐3p) in PASMCs, which is sorted into multivesicular bodies (MVBs) and released into the extracellular space as EVs. These miR‐143‐3p containing EVs are taken up by PAECs, followed by enhanced cell migration and defective angiogenesis and thereby contribute to the development of pulmonary artery hypertension 5,21,140,176,181,205. Red arrowed line, activation; green line with T end, inhibition.


Figure 1. Possible mechanisms of the biogenesis of exosomes (EXOs) and microvesicles (MVs). The biogenesis of EXOs starts from the early endosomes (EE) derived from the internalized plasma membrane or from the biosynthetic pathway of [the trans‐Golgi network (TGN)]. The cargos on the membrane of the endosomes are sorted, followed by budding inwards and fission into small membrane vesicles known as intraluminal vesicles (ILVs) within the lumen of endosomes during their maturation into multivesicular bodies (MVBs). These processes are conducted in a manner dependent or independent of the endosomal sorting complex required for transport (ESCRT) complex. The MVB can either follow a degradation pathway fusing with lysosomes or proceed to release the ILVs as exosomes to the extracellular space. The cytosolic pH may affect MVB function as secretory versus degradatory compartments. For the extracellular release of exosomes, MVBs are first transported to the plasma membranes, a process dependent on the cytoskeleton and regulated by Rab GTPases including Rab27b and Rab35. MVBs are then docked on the plasma membrane that involves the rearrangement of sub‐membrane actin cytoskeleton in a manner depends on Rab27a and Rab11. This is followed by the fusion of MVBs with the plasma membrane that leads to the formation of pores in the membrane to release exosomes. This may be mediated by soluble N‐ethylmaleimide‐sensitive factor attachment protein receptor (SNARE) proteins and the Ca2+ sensor synaptotagmin (Syt). The microvesicles (MVs) are formed by clustering and sorting of various components in discrete membrane microdomains of the plasma membrane followed by outward budding of the plasma membrane and the release of the MVs. In the clustering and sorting process, ESCRT‐I and tetraspanin may act as key mediators. Concomitant to this process the membrane microdomains of the plasma membrane undergo lipid flipping, that is, exposition of phosphatidylserine and phosphatidylethanolamine from the inner leaflet to the cell surface. Subsequently, the membrane microdomains of the plasma membrane bud outwards and are released as MVs. This process is orchestrated by ESCRT‐III, the small GTPase RhoA and Rho‐associated protein kinase (ROCK) as well as ADP‐ribosylation factor 6 (ARF6), which are involved in actin polymerization and myosin activity in the processes in MV release 61,66,72,73,119,137,141,156,185,187.


Figure 2. Extracellular vesicle (EV) interactions with target cells. EVs can transmit information to target cells by directly binding to cell surface receptors to evoke intracellular signaling without delivery of their content, fusing with the plasma membrane or through endocytosis to deliver their content. The fusion of EVs with the plasma membrane leads to delivery of their content (including protein, peptide, mRNA, miRNA, etc.), which is followed by altered cellular activities including changes in gene transcription. EVs can also be taken up entirely by target cells through various forms of endocytosis. Exosomes and small ectosomes can be internalized via caveolae, clathrin‐coated pits, or lipid rafts; whereas larger ectosomes or aggregated EVs are internalized through phagocytosis or macropinocytosis (a form of endocytosis by which a large fluid‐filled vesicle is pinched off from the cell membrane into the cytoplasm of the cell). The endocytosed EVs are first located in early endosomes (EE). During the maturation of EEs into multivesicular bodies (MVBs), they are transformed into intraluminal vesicles (ILVs) and their intraluminal contents may be released into the cytosol, which is known as back fusion, a process of major importance for delivery of intraluminal cargoes such as miRNAs. EVs may also be degraded when MVBs are fused with the lysosome so that their contents are recycled to fuel the metabolism of the recipient cells 14,26,61,83,84,119,125,147,178,185.


Figure 3. Different signaling pathways mediated by extracellular vesicles (EVs) in the inflammatory response of the lung evoked by infection (lipopolysaccharide/Gram‐negative bacteria) versus oxidative stress (hyperoxia). Infection primarily stimulates alveolar macrophages to release EVs that carry increased levels of microRNA (miR)‐221 and miR‐222 while oxidative stress predominantly stimulates type‐I epithelial cells to release EVs that carry increased levels of miR‐17, miR‐221, miR‐320a. EVs generated in response to infection and oxidative stress both promote the recruitment of macrophages and the development of lung inflammation. However, EVs derived from alveolar macrophages increase the expression of TLR6, MyD88, IL‐1β, IL‐10, and CD80 in recruited alveolar macrophages. By contrast, EVs released from epithelial cells increase the expression of TLR2, MyD88, TNFα, and IL‐6 in recruited alveolar macrophages 10,37,39,100,114,209. CD80, cluster of differentiation 80. IL‐1β, IL‐6, and IL‐10, interleukin‐1β, ‐6, and ‐10, respectively. MyD88, myeloid differentiation factor 88. TLR2 and TLR6, Toll‐like receptor 2, and 6, respectively. TNFα, tumor necrosis factor α.


Figure 4. Possible mechanism for extracellular vesicles (EVs)‐mediated pulmonary vascular remodeling caused by hypoxia and transforming growth factor β (TGF‐β). When exposed to these stimuli pulmonary artery endothelial cells (PAECs) show an increased release of caveolin‐1 positive (Cav‐1+) EVs, which stimulate the production of TGF‐β from macrophages. TGF‐β causes endothelial cells (ECs) to migrate and elicit defective angiogenesis. It also stimulates pulmonary artery smooth muscle cells (PASMCs) to migrate and inhibits their apoptosis. These effects result from the binding to TGF‐β receptors (TGFβR), phosphorylation of Smad2/3, and altered gene expression. The effect of TGF‐β can be counteracted by bone morphogenetic protein (BMP), which inhibits vascular remodeling through binding to BMP receptor type 2 (BMPR2) followed by phosphorylation of Smad1/5/8 and altered gene expression. However, the shedding of Cav‐1+ EVs caused by hypoxia and TGF‐β may lead to dysfunction of endothelial nitric oxide synthase (eNOS) and increased production of peroxynitrite (OONO−), which suppress the expression of BMPR2 and thus vascular remodeling. Under hypoxia and TGF‐β there is also an increased generation of microRNA 143‐3p (miR‐143‐3p) in PASMCs, which is sorted into multivesicular bodies (MVBs) and released into the extracellular space as EVs. These miR‐143‐3p containing EVs are taken up by PAECs, followed by enhanced cell migration and defective angiogenesis and thereby contribute to the development of pulmonary artery hypertension 5,21,140,176,181,205. Red arrowed line, activation; green line with T end, inhibition.
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Article Title: Extracellular Vesicles as Unique Signaling Messengers: Role in Lung Diseases
 

How to Cite

Yuansheng Gao, J. Usha Raj. Extracellular Vesicles as Unique Signaling Messengers: Role in Lung Diseases. Compr Physiol 2020, 11: 1351-1369. doi: 10.1002/cphy.c200006