Macrophages Facilitate Electrical Conduction in the Heart

Maarten Hulsmans, Sebastian Clauss, Ling Xiao, Aaron D. Aguirre, Kevin R. King, Alan Hanley, William J. Hucker, Eike M. Wülfers, Gunnar Seemann, Gabriel Courties, Yoshiko Iwamoto, Yuan Sun, Andrej J. Savol, Hendrik B. Sager, Kory J. Lavine, Gregory A. Fishbein, Diane E. Capen, Nicolas Da Silva, Lucile Miquerol, Hiroko WakimotoChristine E. Seidman, Jonathan G. Seidman, Ruslan I. Sadreyev, Kamila Naxerova, Richard N. Mitchell, Dennis Brown, Peter Libby, Ralph Weissleder, Filip K. Swirski, Peter Kohl, Claudio Vinegoni, David J. Milan, Patrick T. Ellinor, Matthias Nahrendorf

Research output: Contribution to journalArticle

245 Scopus citations

Abstract

Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11bDTR mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction.

Original languageEnglish
Pages (from-to)510-522.e20
JournalCell
Volume169
Issue number3
DOIs
StatePublished - Apr 20 2017

Keywords

  • atrioventricular node
  • computational modeling
  • connexin 43
  • electrical conduction
  • gap junctions
  • heart
  • macrophages
  • optogenetics
  • single-cell RNA-sequencing
  • tissue clearing

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  • Cite this

    Hulsmans, M., Clauss, S., Xiao, L., Aguirre, A. D., King, K. R., Hanley, A., Hucker, W. J., Wülfers, E. M., Seemann, G., Courties, G., Iwamoto, Y., Sun, Y., Savol, A. J., Sager, H. B., Lavine, K. J., Fishbein, G. A., Capen, D. E., Da Silva, N., Miquerol, L., ... Nahrendorf, M. (2017). Macrophages Facilitate Electrical Conduction in the Heart. Cell, 169(3), 510-522.e20. https://doi.org/10.1016/j.cell.2017.03.050