title: Differential requirement for ROCK in dendritic cell migration within lymphatic capillaries in steady-state and inflammation.
abstract: Dendritic cell (DC) migration via lymphatic vessels to draining lymph nodes (dLNs) is crucial for the initiation of adaptive immunity. We imaged this process by intravital microscopy (IVM) in the ear skin of transgenic mice bearing red-fluorescent vasculature and yellow-fluorescent DCs. DCs within lymphatic capillaries were rarely transported by flow, but actively migrated within lymphatics and were significantly faster than in the interstitium. Pharmacologic blockade of the Rho-associated protein kinase (ROCK), which mediates nuclear contraction and de-adhesion from integrin ligands, significantly reduced DC migration from skin to dLNs in steady-state. IVM revealed that ROCK blockade strongly reduced the velocity of interstitial DC migration, but only marginally affected intralymphatic DC migration. By contrast, during tissue inflammation, ROCK blockade profoundly decreased both interstitial and intralymphatic DC migration. Inhibition of intralymphatic migration was paralleled by a strong up-regulation of ICAM-1 in lymphatic endothelium, suggesting that during inflammation ROCK mediates de-adhesion of DC-expressed integrins from lymphatic-expressed ICAM-1. Flow chamber assays confirmed an involvement of lymphatic-expressed ICAM-1 and DC-expressed ROCK in DC crawling on lymphatic endothelium. Overall, our findings further define the role of ROCK in DC migration to dLNs and reveal a differential requirement for ROCK in intralymphatic DC crawling during steady-state and inflammation.
authors.affiliation: Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Switzerland.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Nitschké
authors.forename: David
authors.initials: D
authors.lastname: Aebischer
authors.forename: Michael
authors.initials: M
authors.lastname: Abadier
authors.forename: Simone
authors.initials: S
authors.lastname: Haener
authors.forename: Matije
authors.initials: M
authors.lastname: Lucic
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vigl
authors.forename: Hervé
authors.initials: H
authors.lastname: Luche
authors.forename: Hans Jörg
authors.initials: HJ
authors.lastname: Fehling
authors.forename: Oliver
authors.initials: O
authors.lastname: Biehlmaier
authors.forename: Ruth
authors.initials: R
authors.lastname: Lyck
authors.forename: Cornelia
authors.initials: C
authors.lastname: Halin
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D003433:Crosses, Genetic; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003877:Dermatitis, Contact / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004729:Endothelium, Lymphatic / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011828:Radiation Chimera; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D015815:Cell Adhesion Molecules; C090509:Icam1 protein, mouse; D008164:Luminescent Proteins; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D018799:Intercellular Adhesion Molecule-1; D054460:rho-Associated Kinases