Blocking Inflammatory Cells at the Entry Point: Mouse Psoriasis Study Targets High Endothelial Venules

Treating chronic inflammation may not necessarily require targeting immune cells themselves. A research team from VIB, KU Leuven, and other institutions instead focused on the specialized blood vessels that immune cells must pass through before entering tissues, and found in mice with psoriasis that altering this “traffic entry point” could reduce cell accumulation and skin inflammation. The study has been published in *Immunity*.

These blood vessels are called high endothelial venules (HEVs). They primarily help lymphocytes in the blood enter lymph nodes; during inflammation, their networks expand, and they may also appear in ectopic lymphoid-like tissues such as psoriasis lesions. Peripheral node addressin (PNAd) on the surface of HEVs acts as an adhesion marker, capturing lymphocytes that carry L-selectin and guiding them out of the bloodstream.

The team combined single-cell transcriptomics, unbiased proteomics, intravital imaging, and an inducible HEV-tracing system to analyze the mechanisms that maintain the identity of these blood vessels. The results showed that cellular autophagy is not merely a recycling system that removes damaged components; it also supports lymphotoxin β receptor (LTβR) signaling and the unfolded protein response, enabling HEVs to continue producing PNAd and maintain their specialized morphology.

When the researchers disrupted autophagy in mouse HEVs, PNAd production decreased, the normally thicker endothelial cells became flatter, the blood vessels gradually lost their HEV characteristics, and lymphocyte homing was correspondingly weakened. In a model of psoriasis-like skin inflammation, this change reduced lymphocyte and neutrophil recruitment, cytokine release, and skin inflammation.

The research team further blocked LTβR pharmacologically and obtained results similar to those caused by defective autophagy. This makes LTβR a candidate node that may be easier to target and suggests a therapeutic concept distinct from directly suppressing immune cells or inflammatory cytokines: first reduce the ability of blood vessels at lesions to recruit immune cells, thereby limiting at the source the flow of cells that sustains inflammation.

However, all current evidence comes from mice and does not yet demonstrate that this approach can preserve normal immune defenses in humans. Clinical data on dosage, safety, and long-term effects are also lacking. Autophagy may play different, or even opposite, anti-inflammatory roles in ordinary vascular endothelium. Whether future drugs can precisely target disease-causing HEVs without disrupting normal immune surveillance in lymph nodes will therefore be a critical test before this approach can advance toward the treatment of psoriasis or other autoimmune diseases.