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 trafficking in secondary lymphoid organs.
• HEVs facilitate adaptive immune responses by enabling lymphocyte homing via L-selectin ligands.
• Mechanisms maintaining HEV structure and function during inflammation are not fully understood.

Purpose of the Study:

• To investigate the role of autophagy in maintaining HEV function and expansion during inflammation.
• To elucidate the molecular pathways linking autophagy to 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 mouse model of psoriasis.

Main Results:

• Autophagy deficiency disrupted lymphotoxin beta receptor (LTβR) signaling and the unfolded protein response in HEVs.
• Impaired autophagy led to reduced peripheral node addressin (PNAd) production, HEV dedifferentiation, and compromised lymphocyte homing.
• Autophagy deficiency and LTβR blockade reduced skin inflammation by limiting immune cell infiltration and cytokine release in mice.

Conclusions:

• Autophagy is crucial for preserving HEV identity and function.
• Autophagy safeguards HEV integrity, ensuring efficient lymphocyte homing and immune surveillance.
• Targeting autophagy may offer therapeutic strategies for inflammatory skin diseases like psoriasis.