Inflamed endothelial cells express S1PR1 inhibitor CD69 to induce vascular leak

Area of Science:

• Endothelial biology
• Immunology
• Vascular physiology

Background:

• Endothelial barrier dysfunction contributes to inflammation and tissue damage.
• Sphingosine 1-phosphate receptor-1 (S1PR1) is crucial for endothelial junction integrity and barrier function.
• Cytokines like TNFα and TLR agonists can activate endothelial cells.

Purpose of the Study:

• To investigate the role of CD69 in endothelial cells during inflammation and viral infections.
• To elucidate the mechanism by which CD69 affects endothelial barrier function and S1PR1 signaling.
• To determine if CD69 contributes to vascular leakage in vivo.

Main Methods:

• Activation of endothelial cells (ECs) with TNFα and polyinosine/polycytosine (pI:C).
• Analysis of CD69 induction via the NFκB pathway.
• Assessment of S1PR1 endocytosis, signaling, and barrier function.
• In vivo studies using viral infections (H1N1, MHV-A59) and adeno-associated virus-mediated gene delivery in mice.
• Genetic mouse models lacking endothelial CD69.

Main Results:

• ECs activated by TNFα and pI:C induce CD69 through the NFκB pathway.
• Endothelial CD69 promotes S1PR1 endocytosis, inhibiting downstream signaling and barrier function.
• Viral infections (H1N1, MHV-A59) and TLR agonists induce CD69 in lung ECs.
• Overexpression of CD69 in lung ECs decreases S1PR1 and claudin-5, increasing vascular permeability.
• Mice lacking endothelial CD69 exhibit reduced lung vascular leak during H1N1 infection.

Conclusions:

• Endothelial activation during inflammation and viral defense induces CD69, which downregulates S1PR1, leading to vascular leakage.
• CD69 antagonizes the protective S1PR1 pathway in ECs, potentially exacerbating inflammation.
• Targeting CD69 may offer a therapeutic strategy to mitigate vascular leakage in inflammatory conditions and infections.