Autophagy maintains HEV identity and function during inflammation

Summary High endothelial venules (HEVs) play a crucial role in adaptive immune responses in secondary and tertiary lymphoid organs. They are uniquely equipped with high levels of peripheral node addressins (PNAd), harboring carbohydrate structures that serve as L-Selectin ligands to efficiently facilitate lymphocyte homing. During inflammation, the HEV network expands in SLOs, increasing lymphocyte infiltration, but the underlying mechanisms maintaining HEVs remain underexplored. Here, we report that autophagy is essential for HEV function and expansion. Using single-cell transcriptomics, intravital imaging, and an inducible HEV tracer system in mice, we demonstrate that autophagy deficiency compromises LTβR-signaling and the Unfolded Protein Response in HEVs, leading to disrupted PNAd production, dedifferentiation, and reduced lymphocyte homing. Autophagy deficiency and LTβR blockade impaired HEV function and reduced skin inflammation in psoriasis-bearing mice by limiting immune infiltration and cytokine release. Our work uncovers an unprecedented role of autophagy in safeguarding HEV identity and function during inflammation. Highlights High endothelial venules (HEVs) exhibit heightened autophagy in comparison to non-HEV blood endothelial cells, which further increases during inflammation. Autophagy is pivotal in maintaining HEV fate and function, specifically during inflammation, via LTβR signaling and the Unfolded Protein Response (UPR), ensuring the proper production of peripheral node addressins (PNAd) that serve as L-selectin ligands for the efficient influx of naïve lymphocytes. Blocking autophagy in HEVs leads to disrupted PNAd production, HEV flattening and dedifferentiation, and reduced lymphocyte homing. Genetic and pharmacological perturbation of HEV function in the lymph nodes and skin lesions of psoriasis-bearing mice impaired neutrophil and lymphocyte recruitment, as well as cytokine secretion, thereby alleviating skin inflammation.