Blood Journal
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Discoidin domain receptor 2 regulates neutrophil chemotaxis in 3D collagen matrices

  1. Philippe V. Afonso1,
  2. Colin P. McCann1,2,
  3. Senta M. Kapnick1,3, and
  4. Carole A. Parent1
  1. 1Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
  2. 2Department of Physics, University of Maryland College Park, College Park, MD; and
  3. 3Department of Biology, Johns Hopkins University, Baltimore, MD

Key Points

  • DDR2 regulates the directional migration of neutrophils in 3D collagen matrices, but not on 2D surfaces.

  • DDR2 regulates directionality through increased metalloproteinase secretion and generation of collagen-derived chemotactic peptide gradients.

Abstract

Neutrophils express a variety of collagen receptors at their surface, yet their functional significance remains unclear. Although integrins are essential for neutrophil adhesion and migration on 2-dimensional (2D) surfaces, neutrophils can compensate for the absence of integrins in 3-dimensional (3D) lattices. In contrast, we demonstrate that the inhibition of the tyrosine-kinase collagen receptor discoidin domain receptor 2 (DDR2) has no impact on human primary neutrophil migration on 2D surfaces but is an important regulator of neutrophil chemotaxis in 3D collagen matrices. In this context, we show that DDR2 activation specifically regulates the directional migration of neutrophils in chemoattractant gradients. We further demonstrate that DDR2 regulates directionality through its ability to increase secretion of metalloproteinases and local generation of collagen-derived chemotactic peptide gradients. Our findings highlight the importance of collagen-derived extracellular signaling during neutrophil chemotaxis in 3D matrices.

  • Submitted August 22, 2012.
  • Accepted November 21, 2012.
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