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The calcium-activated nonselective cation channel TRPM4 is essential for the migration but not the maturation of dendritic cells

Nature Immunology volume 9, pages 1148–1156 (2008)Cite this article

Abstract

Dendritic cell (DC) maturation and migration are events critical for the initiation of immune responses. After encountering pathogens, DCs upregulate the expression of costimulatory molecules and subsequently migrate to secondary lymphoid organs. Calcium (Ca2+) entry governs the functions of many hematopoietic cell types, but the role of Ca2+ entry in DC biology remains unclear. Here we report that the Ca2+-activated nonselective cation channel TRPM4 was expressed in and controlled the Ca2+ homeostasis of mouse DCs. The absence of TRPM4, which elicited Ca2+ overload, did not influence DC maturation but did considerably impair chemokine-dependent DC migration. Our results establish TRPM4-regulated Ca2+ homeostasis as crucial for DC mobility but not maturation and emphasize that DC maturation and migration are independently regulated.

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Figure 1: DC populations in TRPM4-deficient and littermate control mice.
Figure 2: Impaired migration of DCs in Trpm4−/− mice.
Figure 3: A TRPM4-like current is present in Trpm4+/+ BMDCs but not in Trpm4−/− BMDCs.
Figure 4: TRPM4 is the main DC CAN channel regulating Ca2+ signaling.
Figure 5: Identical differentiation and maturation of Trpm4−/− and Trpm4+/+ BMDCs.
Figure 6: Greater mobility but less chemotaxis of Trpm4−/− iDCs.
Figure 7: PLC-β2 downregulation induced by Ca2+ overload in Trpm4−/− DCs.

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Acknowledgements

We thank S.Y. Lin (ABgenomics) and B. Koller (University of North Carolina) for help with generation of Trpm4−/−mice; C.S. Zuker (University of California, San Diego) for Trpm5−/− mice; E. Ferrary for help with the patch-clamp setup; M. Benhamou and U. Blank for advice and critical reading of the manuscript; and J. Bex, A. Bouhalfaïa and E. Couchi for help in animal care. Supported by the Association pour la Recherche sur le Cancer (G.B.), Institut National de la Santé et de la Recherche Médicale (M.D. and P.L.), Ministère de l'Enseignement Supérieur et de la Recherche, Université Paris 7 (N.S.), Fondation pour la Recherche Médicale (T.L. and P.L.) and Action Concertée Incitative Jeunes Chercheurs (P.L.).

Author information

Author notes

  1. Gaëtan Barbet, Marie Demion and Ivan C Moura: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale U699, Paris, F-75018, France

    Gaëtan Barbet, Marie Demion, Ivan C Moura, Nicolas Serafini, Thibaut Léger, François Vrtovsnik, Renato C Monteiro & Pierre Launay

  2. Equipe Avenir, Institut National de la Santé et de la Recherche Médicale, Paris, F-75018, France

    Gaëtan Barbet, Marie Demion, Nicolas Serafini, Thibaut Léger & Pierre Launay

  3. Université Paris 7-Denis Diderot, Faculté de Médecine, Site Xavier Bichat, Paris, F-75018, France

    Gaëtan Barbet, Marie Demion, Ivan C Moura, Nicolas Serafini, Thibaut Léger, François Vrtovsnik, Renato C Monteiro & Pierre Launay

  4. Hôpital Bichat, Service de Néphrologie, Paris, F-75018, France

    François Vrtovsnik

  5. Laboratoire de Physiologie Cellulaire, EA 3212, Université de Caen, Caen, F-14032, France

    Romain Guinamard

  6. Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, 02215, Massachusetts, USA

    Jean-Pierre Kinet

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Contributions

G.B. and I.C.M. were responsible for all experiments involving in vivo analysis of Trpm4−/− and Trpm5−/− mice; M.D. did the electrophysiological experiments in the whole-cell configuration; R.G. did the electrophysiological experiments in the 'inside-out' configuration; G.B. and M.D. did Ca2+ imaging; G.B. did the Transwell assays; M.D. did the time-lapse experiments; T.L. contributed to biochemical experiments; N.S. was responsible for quantitative RT-PCR; G.B. and N.S. were responsible for genotyping of mice; J.-P.K. was responsible for the generation of Trpm4−/− mice, critical reading and comments; R.C.M. and F.V. provided experimental guidance; all authors critically reviewed and contributed to the manuscript; and P.L. directed and supervised all aspects of the study and the writing and editing of the manuscript.

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Correspondence to Pierre Launay.

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Barbet, G., Demion, M., Moura, I. et al. The calcium-activated nonselective cation channel TRPM4 is essential for the migration but not the maturation of dendritic cells. Nat Immunol 9, 1148–1156 (2008). https://doi.org/10.1038/ni.1648

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