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

Abstract

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.