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Published on: March 21, 2021
Microvesicles released from pneumolysin-stimulated lung epithelial cells carry mitochondrial cargo and suppress
E Letsiou1,2, L G Teixeira Alves3, D Fatykhova3
1Division of Pulmonary Inflammation, and Department of Infectious Diseases and Respiratory Medicine, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117, Berlin, Germany. eletsiou@uic.edu.
Abstract:
Microvesicles (MVs) are cell-derived extracellular vesicles that have emerged as markers and mediators of acute lung injury (ALI). One of the most common pathogens in pneumonia-induced ALI is Streptococcus pneumoniae (Spn), but the role of MVs during Spn lung infection is largely unknown. In the first line of defense against Spn and its major virulence factor, pneumolysin (PLY), are the alveolar epithelial cells (AEC). In this study, we aim to characterize MVs shed from PLY-stimulated AEC and explore their contribution in mediating crosstalk with neutrophils. Using in vitro cell and ex vivo (human lung tissue) models, we demonstrated that Spn in a PLY-dependent manner stimulates AEC to release increased numbers of MVs. Spn infected mice also had higher levels of epithelial-derived MVs in their alveolar compartment compared to control. Furthermore, MVs released from PLY-stimulated AEC contain mitochondrial content and can be taken up by neutrophils. These MVs then suppress the ability of neutrophils to produce reactive oxygen species, a critical host-defense mechanism. Taken together, our results demonstrate that AEC in response to pneumococcal PLY release MVs that carry mitochondrial cargo and suggest that these MVs regulate innate immune responses during lung injury.
Insights
Streptococcus pneumoniae stimulates lung epithelial cells to release microvesicles (MVs). These MVs carry mitochondrial cargo, suppressing neutrophil defenses during acute lung injury (ALI).
Area of Science:
- Cell Biology
- Immunology
- Pulmonary Medicine
Background:
- Microvesicles (MVs) are cell-derived vesicles implicated in acute lung injury (ALI).
- Streptococcus pneumoniae (Spn) is a common cause of pneumonia-induced ALI, but its interaction with MVs is unclear.
- Alveolar epithelial cells (AECs) are key in defending against Spn and its toxin, pneumolysin (PLY).
Purpose of the Study:
- To characterize MVs shed from PLY-stimulated AECs.
- To investigate the role of these MVs in immune cell communication during Spn infection.
Main Methods:
- In vitro AEC cultures and ex vivo human lung tissue models were used.
- Spn and PLY stimulation of AECs.
- Analysis of MV content and uptake by neutrophils.
- Assessment of neutrophil reactive oxygen species production.
Main Results:
- Spn, in a PLY-dependent manner, increased MV release from AECs.
- Epithelial-derived MVs were elevated in the lungs of Spn-infected mice.
- MVs from PLY-stimulated AECs contained mitochondrial components and were internalized by neutrophils.
- These MVs impaired neutrophil reactive oxygen species generation.
Conclusions:
- AECs release MVs containing mitochondrial cargo in response to pneumococcal PLY.
- These MVs modulate innate immune responses by suppressing neutrophil function.
- This highlights a novel mechanism of immune regulation in ALI.
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