Lymphotoxin-beta receptor (LTβR) signaling in lymphatic endothelial cells (LEC) regulates leukocyte afferent lymphatic transendothelial migration (TEM). The function of individual signaling pathways for different leukocyte subsets is currently unknown. Here, we show that LTβR signals predominantly via the constitutive and ligand-driven non-classical NIK pathway. Targeting LTβR-NIK by an LTβR-derived decoy peptide (nciLT) suppresses the production of chemokines CCL21 and CXCL12, and enhances the expression of classical NFκB-driven VCAM-1 and integrin β4 to retain T cells on LEC and precludes T cell and dendritic cell TEM. nciLT inhibits contact hypersensitivity (CHS) at both the sensitization and elicitation stages, likely by inhibiting leukocyte migration. By contrast, targeting LTβR-classical NFκB signaling during the elicitation and resolution stages attenuates CHS, possibly by promoting leukocyte egress. These findings demonstrate the importance of LTβR signaling in leukocyte migration and LEC and lymphatic vessel function, and show that antagonist peptides may serve as lead compounds for therapeutic applications. Lymphotoxin beta receptor (LTβR) signalling regulates leukocyte migration through the lymphatic endothelial layers. Here, the authors show that treatment of an LTβR-derived decoy peptide can target the non-classical NFκB pathway to inhibit T cell and dendritic cell migration and ameliorate contact hypersensitivity in mouse models.
【저자키워드】 Inflammatory diseases, NF-kappaB, Tumour-necrosis factors, lymphatic vessels,