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Netrin-1 Reduces Monocyte and Macrophage Chemotaxis towards the Complement Component C5a

Author

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  • Lewis Taylor
  • Maximillian Hugo Brodermann
  • David McCaffary
  • Asif Jilani Iqbal
  • David R Greaves

Abstract

Netrin-1, acting at its cognate receptor UNC5b, has been previously demonstrated to inhibit CC chemokine-induced immune cell migration. In line with this, we found that netrin-1 was able to inhibit CCL2-induced migration of bone marrow derived macrophages (BMDMs). However, whether netrin-1 is capable of inhibiting chemotaxis to a broader range of chemoattractants remains largely unexplored. As our initial experiments demonstrated that RAW264.7 and BMDMs expressed high levels of C5a receptor 1 (C5aR1) on their surface, we aimed to determine the effect of netrin-1 exposure on monocyte/macrophage cell migration induced by C5a, a complement peptide that plays a major role in multiple inflammatory pathologies. Treatment of RAW264.7 macrophages, BMDMs and human monocytes with netrin-1 inhibited their chemotaxis towards C5a, as measured using two different real-time methods. This inhibitory effect was found to be dependent on netrin-1 receptor signalling, as an UNC5b blocking antibody was able to reverse netrin-1 inhibition of C5a induced BMDM migration. Treatment of BMDMs with netrin-1 had no effect on C5aR1 proximal signalling events, as surface C5aR1 expression, internalisation and intracellular Ca2+ release following C5aR1 ligation remained unaffected after netrin-1 exposure. We next examined receptor distal events that occur following C5aR1 activation, but found that netrin-1 was unable to inhibit C5a induced phosphorylation of ERK1/2, Akt and p38, pathways important for cellular migration. Furthermore, netrin-1 treatment had no effect on BMDM cytoskeletal rearrangement following C5a stimulation as determined by microscopy and real-time electrical impedance sensing. Taken together these data highlight that netrin-1 inhibits monocyte and macrophage cell migration, but that the mechanism behind this effect remains unresolved. Nevertheless, netrin-1 and its cognate receptors warrant further investigation as they may represent a potential avenue for the development of novel anti-inflammatory therapeutics.

Suggested Citation

  • Lewis Taylor & Maximillian Hugo Brodermann & David McCaffary & Asif Jilani Iqbal & David R Greaves, 2016. "Netrin-1 Reduces Monocyte and Macrophage Chemotaxis towards the Complement Component C5a," PLOS ONE, Public Library of Science, vol. 11(8), pages 1-22, August.
    • Handle: RePEc:plo:pone00:0160685
    DOI: 10.1371/journal.pone.0160685
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    References listed on IDEAS

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    1. Ruslan Medzhitov, 2008. "Origin and physiological roles of inflammation," Nature, Nature, vol. 454(7203), pages 428-435, July.
    2. Landin Boring & Jennifa Gosling & Michael Cleary & Israel F. Charo, 1998. "Decreased lesion formation in CCR2−/− mice reveals a role for chemokines in the initiation of atherosclerosis," Nature, Nature, vol. 394(6696), pages 894-897, August.
    3. Asif J Iqbal & Daniel Regan-Komito & Ivy Christou & Gemma E White & Eileen McNeill & Amy Kenyon & Lewis Taylor & Theodore S Kapellos & Edward A Fisher & Keith M Channon & David R Greaves, 2013. "A Real Time Chemotaxis Assay Unveils Unique Migratory Profiles amongst Different Primary Murine Macrophages," PLOS ONE, Public Library of Science, vol. 8(3), pages 1-12, March.
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