# Endothelium‐Treg Communication Through Extracellular Vesicle Transfer Exacerbates Acute Respiratory Distress Syndrome

## TL;DR

This study shows that lung endothelial cells release extracellular vesicles that weaken regulatory T cells, worsening lung inflammation in ARDS.

## Contribution

The study identifies a novel mechanism where endothelial cell-derived extracellular vesicles containing Med1 suppress Tregs through IL-21 induction in ARDS.

## Key findings

- Endothelial cell-derived EVs suppress Treg function and increase IL-21 production in acute lung injury models.
- Med1 in EVs binds to the IL-21 gene promoter, activating its transcription in Tregs.
- Reducing Med1 in EVs reverses Treg suppression and alleviates lung inflammation in ARDS.

## Abstract

Decreased percentage of Foxp3+ regulatory T cells (Tregs) in the lungs results in overwhelming inflammation and delayed recovery of acute lung injury (ALI) caused by acute respiratory distress syndrome (ARDS). Extracellular vesicles (EVs) in the pulmonary microenvironment significantly affect the immune system, but their underlying effects on Tregs are unclear. Here, we demonstrate increased endothelial cell‐derived EVs (CD31+ EVs) in lipopolysaccharide (LPS)‐induced ALI models by single‐EV analysis. EVs from activated pulmonary endothelial cells (ECs) exhibit proinflammatory effects and suppress Treg induction. Exposure of Tregs to these EVs induces massive production of interleukin (IL)‐21, which has been proven to reduce Foxp3 expression. Mechanistically, we find that Med1 enriched in these EVs can directly bind to the promoter region of the IL‐21 gene thus activating IL‐21 transcription in Tregs. Moreover, we confirm that suppressing Med1 accumulation in EVs from activated pulmonary ECs can reverse Treg differentiation, and alleviate lung inflammation. Finally, we observe a significant increase of EVs carrying Med1 in the BALF of patients with ARDS. Taken together, this study identifies that EV‐mediated pulmonary endothelium‐Treg communication is crucial for Treg suppression in ARDS and may provide potential therapeutic targets for the treatment of this fatal clinical syndrome.

Here, we reveal that pulmonary endothelium‐derived EVs aggravate lung inflammation via destabilizing Tregs during ALI/ARDS. Mechanistically, Tregs absorbs EV‐Med1, which promotes the secretion of IL‐21. This cytokine in turn induces hyper‐phosphorylation of STAT3 in Tregs thus induing loss of Foxp3, creating an hyperinflammatory ALI/ARDS microenvironment.