Autophagy maintains high endothelial venule identity and function during inflammation

Area of Science:

• Immunology
• Cell Biology
• Vascular Biology

Background:

• High endothelial venules (HEVs) are critical for lymphocyte homing to secondary lymphoid organs (SLOs).
• HEV expansion during inflammation is vital for adaptive immunity but poorly understood.
• Peripheral node addressin (PNAd) on HEVs facilitates lymphocyte binding via L-selectin.

Purpose of the Study:

• To investigate the role of autophagy in maintaining HEV function and expansion during inflammation.
• To elucidate the molecular mechanisms by which autophagy influences HEV identity and lymphocyte homing.

Main Methods:

• Single-cell transcriptomics and unbiased proteomics in mice.
• Intravital imaging and an inducible HEV tracer system.
• Assessment of HEV function in a psoriasis inflammation model.

Main Results:

• Autophagy is crucial for lymphotoxin beta receptor (LTβR) signaling and unfolded protein response in HEVs.
• Autophagy deficiency disrupts PNAd production, leading to HEV dedifferentiation.
• Impaired HEV function due to autophagy deficiency reduces lymphocyte homing and skin inflammation in a psoriasis model.

Conclusions:

• Autophagy is essential for safeguarding HEV identity and function.
• Targeting autophagy may represent a therapeutic strategy for inflammatory skin diseases by modulating immune cell infiltration.