# Influenza Induces Lung Lymphangiogenesis Independent of YAP/TAZ Activity in Lymphatic Endothelial Cells

## TL;DR

Influenza infection causes new lymphatic vessels to form in the lungs of mice, and this process does not rely on YAP/TAZ signaling in lymphatic cells.

## Contribution

The study reveals that YAP/TAZ signaling is not required for lung lymphangiogenesis or immune responses during influenza.

## Key findings

- Influenza A virus infection in mice leads to significant lymphangiogenesis in the lungs.
- Lung lymphatic expansion is driven by proliferation of existing lymphatic endothelial cells.
- YAP/TAZ activity in lymphatic endothelial cells is not necessary for lymphangiogenesis or immune responses during influenza.

## Abstract

The lymphatic system consists of a vessel network lined by specialized lymphatic endothelial cells (LECs) that are responsible for tissue fluid homeostasis and immune cell trafficking. The mechanisms for organ-specific LEC responses to environmental cues are not well understood. We found robust lymphangiogenesis during influenza A virus infection in the adult mouse lung. We show that the number of LECs increases 2-fold at 7 days post-influenza infection (dpi) and 3-fold at 21 dpi, and that lymphangiogenesis is preceded by lymphatic dilation. We also show that the expanded lymphatic network enhances fluid drainage to mediastinal lymph nodes. Using EdU labeling, we found that a significantly higher number of pulmonary LECs are proliferating at 7 dpi compared to LECs in homeostatic conditions. Lineage tracing during influenza indicates that new pulmonary LECs are derived from preexisting LECs rather than non-LEC progenitors. Lastly, using a conditional LEC-specific YAP/TAZ knockout model, we established that lymphangiogenesis, fluid transport and the immune response to influenza are independent of YAP/TAZ activity in LECs. These findings were unexpected, as they indicate that YAP/TAZ signaling is not crucial for these processes.