The leukotriene C(4) transporter MRP1 regulates CCL19 (MIP-3beta, ELC)-dependent mobilization of dendritic cells to lymph nodes.
Adaptive immune responses begin after antigen-bearing dendritic cells (DCs) traffic from peripheral tissues to lymph nodes. Here, we show that DC migration from skin to lymph nodes utilizes the leukotriene C(4) (LTC(4)) transporter multidrug resistance-associated protein 1 (MRP1). DC mobilization from the epidermis and trafficking into lymphatic vessels was greatly reduced in MRP1(-/-) mice, but migration was restored by exogenous cysteinyl leukotrienes LTC(4) or LTD(4). In vitro, these cysteinyl leukotrienes promoted optimal chemotaxis to the chemokine CCL19, but not to other related chemokines. Antagonism of CCL19 in vivo prevented DC migration out of the epidermis. Thus, MRP-1 regulates DC migration to lymph nodes, apparently by transporting LTC(4), which in turn promotes chemotaxis to CCL19 and mobilization of DCs from the epidermis.
Robbiani
D F
DF
Department of Pathology and Immunology Program Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10029, USA.
Finch
R A
RA
Jäger
D
D
Muller
W A
WA
Sartorelli
A C
AC
Randolph
G J
GJ
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement; D002478:Cells, Cultured; D054415:Chemokine CCL19; D019742:Chemokines, CC / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002633:Chemotaxis; D003713:Dendritic Cells / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate / Q000494:pharmacology; D006801:Humans; D015151:Immunoblotting; D020024:Leukotriene Antagonists / Q000494:pharmacology; D017997:Leukotriene C4 / Q000378:metabolism*; D017998:Leukotriene D4 / Q000378:metabolism; D008024:Ligands; D008198:Lymph Nodes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000378:metabolism
D018528:ATP-Binding Cassette Transporters; D054415:Chemokine CCL19; D019742:Chemokines, CC; D016650:Fluorescein-5-isothiocyanate; D020024:Leukotriene Antagonists; D017997:Leukotriene C4; D017998:Leukotriene D4; D008024:Ligands; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; C515460:CCL19 protein, human; C515370:CCR7 protein, human; C515461:Ccl19 protein, mouse; C515371:Ccr7 protein, mouse; C059141:verlukast