JAKinibs prevent persistent, IFNγ-autonomous endothelial cell inflammation and immunogenicity

Area of Science:

• Immunology
• Cellular Biology
• Vascular Biology

Background:

• T cell adhesion and activation are crucial for inflammatory responses and transplant rejection.
• Interferon gamma (IFNγ) enhances endothelial cell (EC) pro-adhesive and costimulatory molecule expression.
• IFNγ-induced EC antigen-presenting capacity persists after cytokine withdrawal.

Purpose of the Study:

• To investigate the intracellular signaling mechanisms mediating chronic endothelial activation by IFNγ.
• To determine the durability of IFNγ signaling in human aortic endothelial cells.
• To identify therapeutic targets for dampening vascular inflammation.

Main Methods:

• Measured gene expression, phenotype, secretome, and JAK/STAT phosphorylation in primary human ECs.
• Utilized chronic and transient IFNγ stimulation with JAK inhibitors.
• Assessed STAT1 transcriptional activity and SOCS expression in IFNγ reporter cells.

Main Results:

• Short IFNγ exposure led to sustained elevation of adhesion molecules and chemokines for up to 48 hours.
• Durable JAK/STAT and interferon response factor expression were dependent on new transcription but independent of continuous IFNγ.
• Persistent STAT transcription and JAK signaling, particularly involving JAK2, were required for the pro-inflammatory EC phenotype post-IFNγ withdrawal.
• SOCS1 failed to be induced in primed ECs, contributing to prolonged inflammatory gene expression.

Conclusions:

• Sustained JAK-dependent endothelial dysfunction occurs after IFNγ exposure.
• Endothelial inflammation resolution is impaired due to persistent JAK/STAT activation and lack of SOCS1 induction.
• JAK inhibitors, particularly those potent against JAK2, may offer therapeutic benefits in vascular inflammation and allogeneic responses.