Lymphotoxin β receptor signaling and CD11c-positive dendritic cells form high endothelial venule-like vessels in the skin in murine atopic dermatitis model

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Abstract High endothelial venules (HEVs), which are characterized by the expression of peripheral node addressin (PNAd), are essential routes for the trafficking of naïve T cells and central memory T cells (Tcms) into secondary lymphoid organs. In lymph nodes (LNs), lymphotoxin (LT) α1β2-LTβ receptor (LTβR) signaling from dendritic cells (DCs) is essential for the formation of HEVs. Although it has been reported that PNAd+ HEV-like vessels appear in the skin under some inflammatory condition, such as atopic dermatitis (AD), the formation mechanism of HEV-like vessels and their functions in the skin have remained unclear. To clarify these issues, we established a system to induce PNAd+ HEV-like vessels in the skin, using a mouse AD model induced by calcipotriol. Flow cytometric (FCM) analysis revealed that around 20–30% of vessels were PNAd+ in the AD-like skin lesions. Electron microscopic analysis showed prominent formation of rough endoplasmic reticulum, Golgi apparatus and mitochondria in the HEV-like vessels similar to HEVs in LNs. These vessels were mainly detected in post-capillary venules, around which dermal DCs formed clusters. Administration of LTβR-Fc fusion protein or inhibition of the DC clusters by either pertussis toxin or depletion of DCs using CD11c diphtheria toxin receptor transgenic mice abolished the formation of HEV-like vessels in the skin. Naïve T cells and Tcms infiltration were detected in both AD patients and murine AD model skin by immunohistochemistry and FCM. Collectively, our results suggest that LTβR signaling and CD11c+ DCs mediate the formation of HEV-like vessels in the skin, which may possess functions of HEV and regulate the transmigration of naïve T cells and Tcms.

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