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S. Lee, M. Kubala, S. Chakravarti; Lumican Regulates Integrin-Mediated Chemotactic Migration of Neutrophils. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1197.
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Lumican (Lum) is a leucine-rich repeat keratan sulfate proteoglycan of the extracellular matrix (ECM). We have shown that 1) lumican regulates toll-like receptor 4-mediated innate immune response and 2) influx of polymorphonuclear neutrophils (PMN) to the injured cornea is reduced and healing delayed in lumican-deficient mice. We investigated the role of lumican in neutrophil migration. Our studies elucidate novel lumican-integrin interactions in promoting PMN migration.
Lum+/+ and Lum-/- peritoneal lavage PMN were tested for migration towards the pro-inflammatory chemokine CXCL1/KC (bottom chamber) in transwells, with or without recombinant lumican (rLum) and function-blocking antibodies against specific integrins (upper chamber). Lumican and integrin interactions were investigated by co-immunoprecipitation and immunofluorescent confocal microscopy.
There was no difference between lumican-deficient and wild type PMN in surface integrins. However, in transwell chemotaxis assays Lum-/- PMN showed reduced migration that could be increased to wild type levels by the addition of rLum. Furthermore, this lumican-aided PMN migration could be inhibited by specific anti-integrin antibodies. Confocal microscopy indicated lumican and integrin proximity on peritoneal PMN surfaces. The co-immunoprecipitation experiments indicated prominent interaction between lumican and specific integrins. Flow cytometry analyses indicated that lumican is not present on bone marrow-derived and circulating PMN. qRT-PCR results revealed that peritoneal PMN do not themselves express lumican. Therefore, peritoneal PMN acquire lumican on the cell surface as they cross the endothelial barrier.
These studies identify a novel paracrine regulation of neutrophil migration by lumican through specific interactions with cell surface integrins.
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