Extracellular matrix lumican deposited on the surface of neutrophils promotes migration by binding to β2 integrin

Seakwoo Lee, Kyle Bowrin, Abdel Rahim Hamad, Shukti Chakravarti

Research output: Contribution to journalArticlepeer-review

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 inPMNmigration. Treatment of PMNs with antibodies that block β 2, β1, and αM integrin subunits inhibits lumican-mediated migration. Furthermore, immunohistochemical and biochemical approaches indicate binding of lumican to β2, αM, and α L integrin subunits. Thus, lumican may regulate PMN migration mediated by MAC-1 (αM2) and LFA-1 (αL2), the two majorPMNsurface integrins.Wedetected 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.

Original languageEnglish (US)
Pages (from-to)23662-23669
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number35
DOIs
StatePublished - Aug 28 2009

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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