This mouse study examined whether autophagy is required for high endothelial venule (HEV) identity and function during inflammation, using single-cell transcriptomics, unbiased proteomics, intravital imaging, and an inducible HEV tracer system.
Autophagy deficiency in HEVs disrupted LTβR signaling and the unfolded protein response, leading to impaired PNAd production, HEV dedifferentiation, and reduced lymphocyte homing; combining autophagy deficiency with LTβR blockade decreased HEV function and skin inflammation in a murine psoriasis model.
All mechanistic findings are from mouse models, limiting direct translation to human HEV biology; the study does not test pharmacological autophagy inhibitors in vivo, only genetic deficiency; the psoriasis model may not fully recapitulate human disease.
Autophagy and LTβR signaling are potential therapeutic targets to limit pathological immune cell infiltration in inflammatory conditions like psoriasis. These findings are preclinical; clinical applicability requires further validation.
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