Autocrine Purinergic Receptor Signaling Is Essential for Macrophage Chemotaxis

Sci. Signal., 27 July 2010
Vol. 3, Issue 132, p. ra55
DOI: 10.1126/scisignal.2000588

Autocrine Purinergic Receptor Signaling Is Essential for Macrophage Chemotaxis

  1. Moritz Kronlage1,
  2. Jian Song2,
  3. Lydia Sorokin2,
  4. Katrin Isfort1,
  5. Tanja Schwerdtle3,
  6. Jens Leipziger4,
  7. Bernard Robaye5,
  8. Pamela B. Conley6,
  9. Hee-Cheol Kim7,
  10. Sarah Sargin1,
  11. Peter Schön8,
  12. Albrecht Schwab1, and
  13. Peter J. Hanley1,*
  1. 1Institut für Physiologie II, Wilhems-Universität Münster, 48149 Münster, Germany.
  2. 2Institut für Physiologische Chemie und Pathobiochemie, Wilhems-Universität Münster, 48149 Münster, Germany.
  3. 3Institut für Lebensmittelchemie, Wilhems-Universität Münster, 48149 Münster, Germany.
  4. 4Institute of Physiology and Biophysics, Aarhus University, 8000 Aarhus, Denmark.
  5. 5Institute of Interdisciplinary Research, Institute of Biology and Molecular Medicine, Université Libre de Bruxelles, 6041 Gosselies, Belgium.
  6. 6Portola Pharmaceuticals, South San Francisco, CA 94080, USA.
  7. 7Angewandte Biophysikalische Chemie, Philipps-Universität Marburg, 35032 Marburg, Germany.
  8. 8Faculty of Science and Technology, Materials Science and Technology of Polymers, 7500 AE Enschede, the Netherlands.
  1. *To whom correspondence should be addressed. E-mail: hanley{at}


Chemotaxis, the movement of cells along chemical gradients, is critical for the recruitment of immune cells to sites of inflammation; however, how cells navigate in chemotactic gradients is poorly understood. Here, we show that macrophages navigate in a gradient of the chemoattractant C5a through the release of adenosine triphosphate (ATP) and autocrine “purinergic feedback loops” that involve receptors for ATP (P2Y2), adenosine diphosphate (ADP) (P2Y12), and adenosine (A2a, A2b, and A3). Whereas macrophages from mice deficient in pannexin-1 (which is part of a putative ATP release pathway), P2Y2, or P2Y12 exhibited efficient chemotactic navigation, chemotaxis was blocked by apyrase, which degrades ATP and ADP, and by the inhibition of multiple purinergic receptors. Furthermore, apyrase impaired the recruitment of monocytes in a mouse model of C5a-induced peritonitis. In addition, we found that stimulation of P2Y2, P2Y12, or adenosine receptors induced the formation of lamellipodial membrane protrusions, causing cell spreading. We propose a model in which autocrine purinergic receptor signaling amplifies and translates chemotactic cues into directional motility.


M. Kronlage, J. Song, L. Sorokin, K. Isfort, T. Schwerdtle, J. Leipziger, B. Robaye, P. B. Conley, H.-C. Kim, S. Sargin, P. Schön, A. Schwab, and P. J. Hanley, Autocrine Purinergic Receptor Signaling Is Essential for Macrophage Chemotaxis. Sci. Signal. 3, ra55 (2010).

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J. Immunol. 190, 774-783 (15 January 2013)

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A. Schwab, A. Fabian, P. J. Hanley, and C. Stock
Physiol. Rev. 92, 1865-1913 (1 October 2012)

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M. Manohar, M. I. Hirsh, Y. Chen, T. Woehrle, A. A. Karande, and W. G. Junger
J. Leukoc. Biol. 92, 787-794 (1 October 2012)

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O. Stettler, R. L. Joshi, A. Wizenmann, J. Reingruber, D. Holcman, C. Bouillot, F. Castagner, A. Prochiantz, and K. L. Moya
Development 139, 215-224 (1 January 2012)

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Z. Shah, T. Kampfrath, J. A. Deiuliis, J. Zhong, C. Pineda, Z. Ying, X. Xu, B. Lu, S. Moffatt-Bruce, R. Durairaj et al.
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JEM 208, 1823-1834 (29 August 2011)

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J. Immunol. 186, 6553-6561 (1 June 2011)

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