Research Article: Activation of endothelial cells by extracellular vesicles derived from Mycobacterium tuberculosis infected macrophages or mice

Date Published: May 31, 2018

Publisher: Public Library of Science

Author(s): Li Li, Yong Cheng, Scott Emrich, Jeffrey Schorey, Selvakumar Subbian.


Endothelial cells play an essential role in regulating an immune response through promoting leukocyte adhesion and cell migration and production of cytokines such as TNFα. Regulation of endothelial cell immune function is tightly regulated and recent studies suggest that extracellular vesicles (EVs) are prominently involved in this process. However, the importance of EVs in regulating endothelial activation in the context of a bacterial infection is poorly understood. To begin addressing this knowledge gap we characterized the endothelial cell response to EVs released from Mycobacterium tuberculosis (Mtb) infected macrophages. Our result showed increased macrophage migration through the monolayer when endothelial cells were pretreated with EVs isolated from Mtb-infected macrophages. Transcriptome analysis showed a significant upregulation of genes involved in cell adhesion and the inflammatory process in endothelial cells treated with EVs. These results were validated by quantitative PCR and flow cytometry. Pathway analysis of these differentially expressed genes indicated that several immune response-related pathways were up-regulated. Endothelial cells were also treated with EVs isolated from the serum of Mtb-infected mice. Interestingly, EVs isolated 14 days but not 7 or 21 days post-infection showed a similar ability to induce endothelial cell activation suggesting a change in EV function during the course of an Mtb infection. Immunofluorescence microscopy result indicated that NF-κB and the Type 1 interferon pathways were involved in endothelial activation by EVs. In summary, our data suggest that EVs can activate endothelial cells and thus may play an important role in modulating host immune responses during an Mtb infection.

Partial Text

Extracellular vesicles (EVs) are important mediators of intercellular communication and are known to carry all the different macromolecules: proteins, carbohydrates, lipids and nucleic acids. Their complex composition allows for engagement of multiple receptors and transfer of numerous cellular components resulting in a marked change in the recipient cell. EVs consist of three major forms: apoptotic bodies, microvesicles, and exosomes. Microvesicles bud from the plasma membrane while exosomes are released from cells upon fusion of a multivesicular body with the plasma membrane and release of the intraluminal vesicles. The composition and function of the different EVs varies and depends on the cell of origin and the physiological state at the time of EV release. Recent studies have focused on the role of EVs in the context of disease pathogenesis and their production and function has been linked to a number of diseases including cancer, cardiovascular and infectious diseases [1, 2]. A significant effort has also focused on EVs as potential biomarkers for various diseases [3–7].

Tuberculosis (TB) is the number one cause of death by a single infectious organism [23]. Approximately one-third of the world’s population are infected with the etiologic agent Mycobacterium tuberculosis with an estimated 9 million new cases and 1.5 million deaths attributed to TB annually [24]. Our inability to control the disease stem in large part from a lack of understanding of what constitutes a protective immune response. It is clear that the host must mount a TH1 response characterized by IFN-ɣ production and activation of naïve macrophages. However, numerous studies have shown that although this TH1 response is necessary for controlling an infection, it is not sufficient and there are other important players in this process such as Th17 cells and ɣδ T cells [25, 26]. The various cytokines such as IL-17 and IL-23 produced by these and other cells are critical for TB control [27, 28]. However, our understanding of what immune responses are necessary for controlling an Mtb infection is clearly incomplete [29, 30]. Recently EVs have garnered significant attention as a new mechanism of immune regulation.




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