Requirement of CCL17 for CCR7- and CXCR4-dependent migration of cutaneous dendritic cells
Edited by Richard A. Flavell, Yale University School of Medicine, Howard Hughes Medical Institute, New Haven, CT, and approved April 1, 2010 (received for review June 8, 2009)
Abstract
Chemokines are known to regulate the steady-state and inflammatory migration of cutaneous dendritic cells (DCs). The β-chemokine CCL17, a ligand of CCR4, is inducibly expressed in a subset of DCs and is strongly up-regulated in atopic diseases. Using an atopic dermatitis model, we show that CCL17-deficient mice develop acanthosis as WT mice, whereas dermal inflammation, T helper 2-type cytokine production, and the allergen-specific humoral immune response are significantly decreased. Notably, CCL17-deficient mice retained Langerhans cells (LCs) in the lesional skin after chronic allergen exposure, whereas most LCs emigrated from the epidermis of allergen-treated WT controls into draining lymph nodes (LNs). Moreover, CCL17-deficient LCs showed impaired emigration from the skin after exposure to a contact sensitizer. In contrast, the absence of CCR4 had no effect on cutaneous DC migration and development of atopic dermatitis symptoms. As an explanation for the major migratory defect of CCL17-deficient DCs in vivo, we demonstrate impaired mobility of CCL17-deficient DCs to CCL19/21 in 3D in vitro migration assays and a blockade of intracellular calcium release in response to CCR7 ligands. In addition, responsiveness of CCL17-deficient DCs to CXCL12 was impaired as well. We demonstrate that the inducible chemokine CCL17 sensitizes DCs for CCR7- and CXCR4-dependent migration to LN-associated homeostatic chemokines under inflammatory conditions and thus plays an important role in cutaneous DC migration.
Acknowledgments
We thank Ingo Uthe and Markus Korkowski for technical help; Cora Schild for technical advice; Heike Weighardt, Charlotte Esser, Jean Krutmann, and Natalija Novak for discussion and comments on the manuscript; and Klaus Pfeffer for generous support. This work was supported by the Deutsche Forschungsgemeinschaft (Grant SFB 704 to I.F. and W.K. and Grant FOR729 to I.F. and B.H.).
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Published online: April 26, 2010
Published in issue: May 11, 2010
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Acknowledgments
We thank Ingo Uthe and Markus Korkowski for technical help; Cora Schild for technical advice; Heike Weighardt, Charlotte Esser, Jean Krutmann, and Natalija Novak for discussion and comments on the manuscript; and Klaus Pfeffer for generous support. This work was supported by the Deutsche Forschungsgemeinschaft (Grant SFB 704 to I.F. and W.K. and Grant FOR729 to I.F. and B.H.).
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This article is a PNAS Direct Submission.
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The authors declare no conflict of interest.
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Requirement of CCL17 for CCR7- and CXCR4-dependent migration of cutaneous dendritic cells, Proc. Natl. Acad. Sci. U.S.A.
107 (19) 8736-8741,
https://doi.org/10.1073/pnas.0906126107
(2010).
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