heparitin-sulfate and Dermatitis--Contact

Circulation of leukocytes via blood, tissue and lymph is integral to adaptive immunity. Afferent lymphatics form CCL21 gradients to guide dendritic cells and T cells to lymphatics and then to draining lymph nodes (dLN). Vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 (VEGFR-3) are the major lymphatic growth factor and receptor. We hypothesized these molecules also regulate chemokine gradients and lymphatic migration.. CD4 T cells were injected into the foot pad or ear pinnae, and migration to afferent lymphatics and dLN quantified by flow cytometry or whole mount immunohistochemistry. Vascular endothelial growth factor receptor 3 or its signaling or downstream actions were modified with blocking monoclonal antibodies (mAbs) or other reagents.. Anti-VEGFR-3 prevented migration of CD4 T cells into lymphatic lumen and significantly decreased the number that migrated to dLN. Anti-VEGFR-3 abolished CCL21 gradients around lymphatics, although CCL21 production was not inhibited. Heparan sulfate (HS), critical to establish CCL21 gradients, was down-regulated around lymphatics by anti-VEGFR-3 and this was dependent on heparanase-mediated degradation. Moreover, a Phosphoinositide 3-kinase (PI3K)α inhibitor disrupted HS and CCL21 gradients, whereas a PI3K activator prevented the effects of anti-VEGFR-3. During contact hypersensitivity, VEGFR-3, CCL21, and HS expression were all attenuated, and anti-heparanase or PI3K activator reversed these effects.. Vascular endothelial growth factor C/VEGFR-3 signaling through PI3Kα regulates the activity of heparanase, which modifies HS and CCL21 gradients around lymphatics. The functional and physical linkages of these molecules regulate lymphatic migration from tissues to dLN. These represent new therapeutic targets to influence immunity and inflammation.

Topics: Adoptive Transfer; Animals; Antibodies, Monoclonal; CD4-Positive T-Lymphocytes; Chemokine CCL21; Chemotaxis, Leukocyte; Dermatitis, Contact; Dinitrofluorobenzene; Disease Models, Animal; Enzyme Activation; Enzyme Activators; Glucuronidase; Heparitin Sulfate; Lymph Nodes; Lymphatic Vessels; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Signal Transduction; Skin; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-3

Primary irritant dermatitis includes an inflammatory process of connective tissue which is of general interest. For the first time this process has been characterised biochemically in humans by following the dermal changes in the concentration of hydroxyproline and four glycosaminoglycans. In healthy individuals (n = 7) and in psoriatics (n = 8) the changes were rather similar. Only dermatan sulphate showed a tendency towards an abnormal response in the psoriatics. In both groups the deviations from the pre-irritant condition clearly distinguished the response of irritant dermatitis from that of the wound healing process: (1) the concentration of hyaluronic acid decreased by the third day and remained so until by the sixth day, (2) after a decrease on the third day the concentration of dermatan sulphate returned to the initial value by the sixth day, (3 and 4) the concentration of chondroitin 4/6-sulphate and heparan sulphate increased continuously from the third to the sixth day, and (5) the concentration of hydroxyproline remained constant throughout the period of investigation.

Topics: Adult; Aged; Benzalkonium Compounds; Chondroitin Sulfates; Dermatan Sulfate; Dermatitis, Contact; Female; Glycosaminoglycans; Heparitin Sulfate; Humans; Hyaluronic Acid; Hydroxyproline; Male; Middle Aged; Psoriasis; Skin