Extracellular matrix lumican deposited on the surface of neutrophils promotes migration by binding to beta2 integrin

J Biol Chem. 2009 Aug 28;284(35):23662-9. doi: 10.1074/jbc.M109.026229. Epub 2009 Jun 15.

Abstract

During inflammation, circulating polymorphonuclear neutrophils (PMNs) receive signals to cross the endothelial barrier and migrate through the extracellular matrix (ECM) to reach the injured site. Migration requires complex and poorly understood interactions of chemokines, chemokine receptors, ECM molecules, integrins, and other receptors. Here we show that the ECM protein lumican regulates PMN migration through interactions with specific integrin receptors. Lumican-deficient (Lum(-/-)) mice manifest connective tissue defects, impaired innate immune response, and poor wound healing with reduced PMN infiltration. Lum(-/-) PMNs exhibit poor chemotactic migration that is restored with exogenous recombinant lumican and inhibited by anti-lumican antibody, confirming a role for lumican in PMN migration. Treatment of PMNs with antibodies that block beta(2), beta(1), and alpha(M) integrin subunits inhibits lumican-mediated migration. Furthermore, immunohistochemical and biochemical approaches indicate binding of lumican to beta(2), alpha(M), and alpha(L) integrin subunits. Thus, lumican may regulate PMN migration mediated by MAC-1 (alpha(M)/beta(2)) and LFA-1 (alpha(L)/beta(2)), the two major PMN surface integrins. We detected lumican on the surface of peritoneal PMNs and not bone marrow or peripheral blood PMNs. This suggests that PMNs must acquire lumican during or after crossing the endothelial barrier as they exit circulation. We also found that peritoneal PMNs do not express lumican, whereas endothelial cells do. Taken together these observations suggest a novel endothelial lumican-mediated paracrine regulation of neutrophils early on in their migration path.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD18 Antigens / genetics
  • CD18 Antigens / immunology
  • CD18 Antigens / metabolism*
  • Cells, Cultured
  • Chemotaxis, Leukocyte*
  • Chondroitin Sulfate Proteoglycans / genetics
  • Chondroitin Sulfate Proteoglycans / immunology
  • Chondroitin Sulfate Proteoglycans / metabolism*
  • Extracellular Matrix / genetics
  • Extracellular Matrix / immunology
  • Extracellular Matrix / metabolism*
  • Female
  • Keratan Sulfate / genetics
  • Keratan Sulfate / immunology
  • Keratan Sulfate / metabolism*
  • Lumican
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / immunology*
  • Neutrophils / metabolism
  • Protein Binding

Substances

  • CD18 Antigens
  • Chondroitin Sulfate Proteoglycans
  • Lum protein, mouse
  • Lumican
  • Keratan Sulfate