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Roger T. Palframan^1,2, Steffen Jung⁴, Guiying Cheng¹, Wolfgang Weninger^1,2, Yi Luo², Martin Dorf², Dan R. Littman⁵, Barrett J. Rollins³, Hans Zweerink⁶, Antal Rot⁷ and Ulrich H. von Andrian^1,2

¹ Center for Blood Research, Harvard Medical School, Boston, MA 02115
² Department of Pathology, Harvard Medical School, Boston, MA 02115
³ Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115
⁴ Molecular Pathogenesis Program, Skirball Institute of Biomolecular Medicine
⁵ Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016
⁶ Merck Research Laboratories, Rahway, NJ 07065
⁷ Novartis Forschungsinstitut, Vienna A-1235, Austria

Address correspondence to Ulrich H. von Andrian, Center for Blood Research, 200 Longwood Ave., Boston, MA 02115. Phone: 617-278-3130; Fax: 617-278-3030; E-mail: uva{at}cbr.med.harvard.edu

Interstitial fluid is constantly drained into lymph nodes (LNs) via afferent lymph vessels. This conduit enables monocyte-derived macrophages and dendritic cells to access LNs from peripheral tissues. We show that during inflammation in the skin, a second recruitment pathway is evoked that recruits large numbers of blood-borne monocytes to LNs via high endothelial venules (HEVs). Inhibition of monocyte chemoattractant protein (MCP)-1 blocked this inflammation-induced monocyte homing to LNs. MCP-1 mRNA in inflamed skin was over 100-fold upregulated and paralleled MCP-1 protein levels, whereas in draining LNs MCP-1 mRNA induction was much weaker and occurred only after a pronounced rise in MCP-1 protein. Thus, MCP-1 in draining LNs was primarily derived from inflamed skin. In MCP-1^-/- mice, intracutaneously injected MCP-1 accumulated rapidly in the draining LNs where it enhanced monocyte recruitment. Intravital microscopy showed that skin-derived MCP-1 was transported via the lymph to the luminal surface of HEVs where it triggered integrin-dependent arrest of rolling monocytes. These findings demonstrate that inflamed peripheral tissues project their local chemokine profile to HEVs in draining LNs and thereby exert "remote control" over the composition of leukocyte populations that home to these organs from the blood.

Key Words: homing • MCP-1 • high endothelial venules • phagocytes • lymphatic system

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